System and method for indicating time elapsed since occurrence of a trigger event

Abstract

Systems and methods are described that can be used to indicate the amount of time that has elapsed since a trigger event occurred. More specifically, the present application relates to systems and methods that can be used to visually indicate the amount of time that has elapsed since an item was removed from its packaging. The system can include an indicator disposed on or within the item and a trigger disposed within the container and in contact with the indicator. The item can be enclosed within a sealable container of the package. The indicator responds to a change in the concentration of the trigger in contact with the indicator. Removal of the item from the container can induce a change in the concentration of the trigger in contact with the indicator. The change in the concentration of the trigger can induce a change in color in the indicator. The color change indicates that a predetermined amount of time has elapsed since the item was removed from the container. The predetermined amount of time can be between 30 minutes and 30 days, for example, between 1 hour and 30 days.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Patent Application No. 16 / 901,113, filed June 15, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Contact lenses are widely used to correct a wide variety of vision defects, including myopia, hyperopia, and astigmatism. Contact lenses can also be used to enhance the natural appearance of the wearer's eyes. Early contact lenses were constructed or made from hard materials and were relatively expensive and fragile. In addition, the materials used to manufacture such hard contact lenses have relatively low oxygen permeability, limiting the flow of oxygen to the conjunctiva and cornea. More recently, soft contact lenses based on hydrogel materials have been developed. Soft contact lenses based on silicone hydrogels exhibit higher oxygen permeability and are generally more comfortable to wear than hard contact lenses.

[0003] Contact lenses made from different materials can have different wear and replacement schedules. "Daily wear" (DW) contact lenses are designed to be worn for one day and removed before sleep. "Extended wear" (EW) contact lenses are typically designed for continuous overnight wear, for up to six consecutive nights. Newer materials, such as silicone hydrogels, can allow for longer wear periods of up to 30 consecutive nights. Such longer-wear lenses are sometimes referred to as "continuous wear" contact lenses (CW). Single-use lenses (sometimes referred to as daily or full-time disposable lenses) are designed to be discarded after a single use. Other disposable contact lenses are designed to be replaced every two or four weeks. Other lenses are designed to be replaced four times a year, twice a year, once a year, or even less regularly.

[0004] Contact lens manufacturers and ophthalmologists have recommended specific replacement times for different types of contact lenses for various reasons. For example, regardless of how well contact lenses are cleaned and maintained, they can accumulate protein, calcium, and / or lipid deposits over time. These deposits can make contact lenses uncomfortable to wear and make the eye more susceptible to infection and irritation. To minimize side effects, wearers need to track lens wear time to ensure timely replacement of contact lenses. However, in the present invention, commercially available lenses do not include a simple indicator to provide the wearer with information that the contact lens has been worn beyond its recommended wear schedule. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, a need exists for a simple system that can be incorporated into contact lenses to notify the wearer that the lenses need to be replaced to prevent the wearer from exceeding the designated replacement interval. [Means for solving the problem]

[0006] Provided herein are systems and methods that can be used to indicate the amount of time that has elapsed since the occurrence of a trigger event. More specifically, the present application relates to systems and methods that can be used to visually indicate, for example, the amount of time that has elapsed since an article was removed from a package, the amount of time that has elapsed since an article or composition was prepared, and / or the amount of time that an article is in use.

[0007] The system may include an indicator disposed on or within the article. The article may be enclosed within a sealable container of the package. The system may further include a trigger disposed within the container and in contact with the indicator. The indicator may respond to a change in concentration of the trigger in contact with the indicator. The trigger may be present in the sealable container at a static concentration.

[0008] Removal of the article from the container can induce a change in the concentration of the trigger in contact with the indicator. The change in the concentration of the trigger can induce an observable change in the indicator. For example, in some embodiments, the indicator can be an optical indicator (e.g., a visible indicator) in which the observable change includes a change in color of the indicator. In such cases, the observable change can be a change in color from a first color within the visible spectrum to a second color within the visible spectrum, a change in color from a first color outside the visible spectrum to a second color within the visible spectrum, or a change in color from a first color within the visible spectrum to a second color outside the visible spectrum. The observable change (e.g., color change) can indicate that a predetermined period of time has elapsed since the article was removed from the container. In some embodiments, the predetermined period of time can be between 30 minutes and 30 days, e.g., between 1 hour and 30 days. Importantly, the observable change can be discrete, such that substantially all of the observable change (e.g., color change) occurs within a predetermined period of time. For example, the observable change may not occur substantially before the predetermined period of time. The observable changes may then occur within a relatively short period of time at and after the predetermined time period, for example, substantially all of the observable changes may occur within 48 hours (e.g., within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 4 hours, within 3 hours, within 2 hours, within 1 hour, or within 30 minutes) of the predetermined time period.

[0009] In some embodiments, a change in the concentration of the trigger can induce two or more observable changes in the indicator to indicate that two or more predetermined periods have elapsed since the item was removed from the container. In some embodiments, the first predetermined period can be between 10 minutes and two weeks, and the second predetermined period is between 30 minutes and 30 days, e.g., between 1 hour and 30 days.

[0010] In some embodiments, the indicator can include a population of nanoparticles stabilized by a capping agent, and the trigger can include a solution containing the capping agent in contact with the indicator. The population of nanoparticles can include a population of plasmonic nanoparticles. In some embodiments, the nanoparticles can have an average particle size of 5 nm to 100 nm as measured by transmission electron microscopy (TEM). In some cases, the population of nanoparticles can have a homogeneous particle shape. In some embodiments, the population of nanoparticles can include a mixture of different particle shapes. The capping agent can be non-covalently associated with the nanoparticles. In certain embodiments, the capping agent can include, for example, a polymer, a surfactant, or a combination thereof.

[0011] In these embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the capping agent can dissociate from the nanoparticles. Dissociation of the capping agent can destabilize the colloidally dispersed nanoparticles and induce aggregation of the nanoparticles. This can result in a change in the color of the nanoparticles. The capping agent can dissociate from the nanoparticles at a rate selected so that the color change indicates that a predetermined period of time has passed since the article was removed from the container.

[0012] In some embodiments, the indicator can include a first population of nanoparticles stabilized by a first capping agent and a second population of nanoparticles stabilized by a second capping agent, and the trigger can include a solution containing the first capping agent and the second capping agent in contact with the indicator. In these embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the first capping agent can dissociate from the first population of nanoparticles at a faster rate than the second capping agent can dissociate from the second population of nanoparticles. The first capping agent can dissociate from the first population of nanoparticles at a first rate. Dissociation of the first capping agent can destabilize the first population of colloidally dispersed nanoparticles and induce aggregation of the first population of nanoparticles. This aggregation can produce a first color change. The second capping agent can dissociate from the second population of nanoparticles at a second rate that is slower than the first rate. The dissociation of the second capping agent can destabilize the second population of colloidally dispersed nanoparticles and induce aggregation of the second population of nanoparticles. This aggregation can produce a second color change. The first and second rates can be selected in combination so that the first and second color changes indicate that two consecutive predetermined periods have elapsed since the item was removed from the container. For example, the first capping agent can dissociate from the first population of nanoparticles at a first rate selected so that the first color change indicates that a first predetermined period has elapsed since the item was removed from the container, and the second capping agent can dissociate from the second population of nanoparticles at a second rate selected so that the second color change indicates that a second predetermined period has elapsed since the item was removed from the container.

[0013] In other embodiments, the indicator can include a chromophore or fluorophore in combination with a dispersing agent, and the trigger can include a solution including the dispersing agent in contact with the indicator. In some embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the dispersing agent dissociates from the chromophore or fluorophore, thereby inducing aggregation of the chromophore and producing a color change (e.g., a red shift), or causing aggregation of the fluorophore and producing a shift in maximum emission wavelength (e.g., a red shift).

[0014] The dispersing agent can dissociate from the chromophore or fluorophore at a rate selected so that a color change or change in maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container. In some embodiments, a change in the concentration of the trigger induces a change in fluorescence in the indicator. The change in fluorescence can include a change in maximum emission wavelength, a change in fluorescence quantum yield, a change in the shape of the emission spectrum, a change in fluorescence lifetime, or a combination thereof.

[0015] In other embodiments, the indicator can include a fluorophore, and the trigger can include a solution including a quencher in contact with the indicator. In some embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the quencher can dissociate from the fluorophore, thereby inducing an increase in fluorescence. The quencher can dissociate from the fluorophore at a rate selected so that the increase in fluorescence indicates that a predetermined period of time has elapsed since the article was removed from the container.

[0016] In other embodiments, the indicator can include a first fluorophore, and the trigger can include a solution including a second fluorophore in contact with the indicator. The first fluorophore and the second fluorophore can comprise a fluorescence resonance energy transfer (FRET) pair. The second fluorophore can dissociate from the first fluorophore, thereby generating a change in maximum emission wavelength. The second fluorophore can dissociate from the first fluorophore at a rate selected such that the change in maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container.

[0017] If desired, the indicator can be suitably packaged so that it remains responsive to changes in the concentration of the trigger when placed on or in the article. In some embodiments, the indicator can be encapsulated in an optically clear tablet. The tablet can be encapsulated in an optically clear tablet that can withstand temperatures above 121°C. g The porous polymer membrane may be formed from a porous polymer membrane formed from a thermoplastic polymer having a pore size large enough to prevent the indicator from passing through the membrane while allowing the trigger to pass through the membrane. A suitable membrane may be selected taking into consideration the identity of the trigger and the identity of the indicator. For example, in embodiments where the indicator comprises a population of nanoparticles stabilized by a capping agent, the porous polymer membrane may have a pore size larger than the capping agent but smaller than the average particle size of the population of nanoparticles. In some examples, the porous polymer membrane may have a pore size of 5 nm to 75 nm.

[0018] In some embodiments, the article comprises a medical or ophthalmic device, such as a contact lens. In some embodiments, the indicator may be autoclave stable. [Brief explanation of the drawings]

[0019] [Figure 1A] FIG. 10 is a schematic diagram of an operating mechanism of one embodiment showing time elapsed based on a trigger event. [Figure 1B]Demonstration of threshold-based color change based on capping agent concentration for purple → red color transition (loss of blue + retention of red) of two particles for manual mixing in a microwell plate is shown. [Figure 1C] Demonstration of programmable color change in dialysis cassettes for color-to-clear transitions is shown. The single particle system was activated for 3 days (Figure 1C), 5 days (Figure 1D), or 8 days (Figure 1E), programmed by the concentration of capping agent. [Figure 1D] Demonstration of programmable color change in dialysis cassettes for color-to-clear transitions is shown. The single particle system was activated for 3 days (Figure 1C), 5 days (Figure 1D), or 8 days (Figure 1E), programmed by the concentration of capping agent. [Figure 1E] Demonstration of programmable color change in dialysis cassettes for color-to-clear transitions is shown. The single particle system was activated for 3 days (Figure 1C), 5 days (Figure 1D), or 8 days (Figure 1E), programmed by the concentration of capping agent. [Figure 2A] The color analysis of the sample shown in Figures 1C-1E demonstrates that the programmable color transitions are discrete and occur rapidly around the target activation time. The G channel of the indicator color was analyzed and normalized to a white background for color analysis. [Figure 2B] The color analysis of the sample shown in Figures 1C-1E demonstrates that the programmable color transitions are discrete and occur rapidly around the target activation time. The G channel of the indicator color was analyzed and normalized to a white background for color analysis. [Figure 2C] The color analysis of the sample shown in Figures 1C-1E demonstrates that the programmable color transitions are discrete and occur rapidly around the target activation time. The G channel of the indicator color was analyzed and normalized to a white background for color analysis. [Figure 3] 1 shows that the activation time of the color indicator is programmable based on the initial concentration of capping agent in the container. Data is shown for a single particle color-to-clear indicator. [Figure 4A] We demonstrate a color-to-color-to-clear (purple-to-red-to-clear) color transition based on a two-particle system (blue star-shaped particles + red spherical particles). The blue particles have lower colloidal stability and are prompted to lose color faster (1 h) than the red particles. Two different red particles were used for programmable color transitions at 1 h and 5 days (Figure 1A) and 1 h and 9 days (Figure 1B), demonstrating that the two color-changing systems can be programmed to activate independently. [Figure 4B] We demonstrate a color-to-color-to-clear (purple-to-red-to-clear) color transition based on a two-particle system (blue star-shaped particles + red spherical particles). The blue particles have lower colloidal stability and are prompted to lose color faster (1 h) than the red particles. Two different red particles were used for programmable color transitions at 1 h and 5 days (Figure 1A) and 1 h and 9 days (Figure 1B), demonstrating that the two color-changing systems can be programmed to activate independently. [Figure 5A] For the red (FIG. 5A) and blue (FIG. 5B) color-changing single particle systems, the indicator is inactive in the presence of a capping agent in the external solution (e.g., while the indicator or article remains in the container). [Figure 5B] For the red (FIG. 5A) and blue (FIG. 5B) color-changing single particle systems, the indicator is inactive in the presence of a capping agent in the external solution (e.g., while the indicator or article remains in the container). [Figure 6] 1 shows a color-bearing particle, in which the capping agent remains attached to the color-bearing particle, including in the absence of the capping agent in the external solution, such that the color-bearing particle provides a constant background for the color-to-color transition. [Figure 7] This is a demonstration of color-to-color (purple-to-red) transition using a two-particle system (blue-loss particles [8-hour program] + color-retaining red particles). [Figure 8A] The incorporation of the indicator into the biomaterial and its stability to autoclaving and various liquids are shown. More specifically, Figure 8A shows a schematic of the formed and sealed micropouch (left) and the two layers of porous polymer sandwiching the encapsulated indicator. [Figure 8B] The incorporation of indicators into biomaterials and their stability to autoclaving and various liquids are shown. More specifically, Figures 8B-8D show schematic side views of sealed micropouches filled with solid blue (Figure 8B), red ring (Figure 8C), and solid red (Figure 8D) indicators incorporated into contact lenses (left) and images of such integrated lenses (right). [Figure 8C] The incorporation of indicators into biomaterials and their stability to autoclaving and various liquids are shown. More specifically, Figures 8B-8D show schematic side views of sealed micropouches filled with solid blue (Figure 8B), red ring (Figure 8C), and solid red (Figure 8D) indicators incorporated into contact lenses (left) and images of such integrated lenses (right). [Figure 8D] The incorporation of indicators into biomaterials and their stability to autoclaving and various liquids are shown. More specifically, Figures 8B-8D show schematic side views of sealed micropouches filled with solid blue (Figure 8B), red ring (Figure 8C), and solid red (Figure 8D) indicators incorporated into contact lenses (left) and images of such integrated lenses (right). [Figure 8E] The incorporation of the indicator into the biomaterial and its stability to autoclaving and various liquids are shown. More specifically, Figures 8E-8F show images of the red (Figure 8E) and purple (Figure 8F) indicators before and after autoclaving, demonstrating their stability to autoclaving. Two replicate samples filled with the red indicator are shown in Figure 8E. [Figure 8F] The incorporation of the indicator into the biomaterial and its stability to autoclaving and various liquids are shown. More specifically, Figures 8E-8F show images of the red (Figure 8E) and purple (Figure 8F) indicators before and after autoclaving, demonstrating their stability to autoclaving. Two replicate samples filled with the red indicator are shown in Figure 8E. [Figure 8G]The incorporation of the indicator into the biomaterial and its stability against autoclaving and various liquids are shown. More specifically, Figure 8G shows the immersion of the red indicator in each solution or PureMoist cleaning solution for up to 35 days, demonstrating its stability against these. DETAILED DESCRIPTION OF THE INVENTION

[0020] It is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description, as the invention is capable of other embodiments and of being practiced or carried out in various ways using the teachings set forth herein.

[0021] definition The following definitions are provided for terms used in this disclosure.

[0022] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. The definition of polymer is consistent with the definition disclosed in Compendium of Polymer Terminology and Nomenclature, IUPAC Recommendations 2008, edited by: Richard G. Jones, Jaroslav Kahovec, Robert Stepto, Edward S. Wilks, Michael Hess, Tatsuki Kitayama, and W. Val Metanomski. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference.

[0023] As used herein, the term "(meth)" refers to optional methyl substitution. Thus, a term such as "(meth)acrylate" refers to both methacrylate and acrylate.

[0024] The term "individual" includes humans and vertebrates.

[0025] The term "ophthalmic device" refers to any apparatus that resides in or on the eye or any part of the eye (including the ocular surface). These devices can provide optical correction, appearance enhancement, vision enhancement, therapeutic effects (e.g., as a bandage), or delivery of active ingredients such as pharmaceutical and nutritional supplements, or any combination of the foregoing. Examples of ophthalmic devices include, but are not limited to, lenses, optics, and ocular inserts (including, but not limited to, punctal plugs). "Lens" includes soft contact lenses, hard contact lenses, hybrid contact lenses, intraocular lenses, and overlay lenses. Ophthalmic devices can include contact lenses.

[0026] The term "contact lens" refers to an ophthalmic device that can be placed on the cornea of ​​an individual's eye. Contact lenses can provide corrective, cosmetic, or therapeutic benefits, including wound healing, delivery of medicinal or nutritional supplements, diagnostic evaluation or monitoring, ultraviolet light blocking, visible light or glare suppression, or a combination thereof. Contact lenses can be of any suitable material known in the art and can be soft lenses, hard lenses, or hybrid lenses containing at least two distinct portions with different physical, mechanical, or optical properties, such as modulus of elasticity, water content, light transmission, or a combination thereof.

[0027] The ophthalmic devices and lenses described herein may be composed of silicone hydrogels or conventional hydrogels, which typically contain at least one hydrophilic monomer and at least one silicone-containing component covalently bonded to each other in the cured device.

[0028] "Target macromolecule" means a macromolecule that has been synthesized from a reactive monomer mixture, including monomers, macromers, prepolymers, crosslinkers, initiators, additives, diluents, and the like.

[0029] The term "polymerizable compound" means a compound containing one or more polymerizable groups. This term includes, for example, monomers, macromers, oligomers, prepolymers, crosslinkers, and the like.

[0030] A "polymerizable group" is a group capable of undergoing chain growth polymerization, such as a carbon-carbon double bond that can polymerize when subjected to free radical and / or cationic polymerization, e.g., radical polymerization initiation conditions. Non-limiting examples of free radical reactive groups include (meth)acrylate, styrene, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, O-vinyl carbamate, O-vinyl carbonate, and other vinyl groups. Preferably, the free radical polymerizable group comprises (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, and styryl functional groups, as well as mixtures of any of the foregoing. More preferably, the free radical polymerizable group comprises (meth)acrylate, (meth)acrylamide, and mixtures thereof. The polymerizable group may be unsubstituted or substituted. For example, the nitrogen atom in (meth)acrylamide may be bonded to hydrogen, or the hydrogen may be substituted with alkyl or cycloalkyl (which may themselves be further substituted).

[0031] Any type of free radical polymerization can be used, including but not limited to bulk, solution, suspension, and emulsion, as well as any controlled radical polymerization method, such as stable free radical polymerization, nitroxide-mediated living polymerization, atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, organotellurium-mediated living radical polymerization, etc.

[0032] A "monomer" is a monofunctional molecule that can undergo chain growth polymerization, particularly free radical polymerization, thereby creating repeating units within the chemical structure of a target macromolecule. Some monomers have difunctional impurities that can act as crosslinkers. A "hydrophilic monomer" is also a monomer that, when mixed with deionized water at 25°C at a concentration of 5 weight percent, gives a clear, single-phase solution. A "hydrophilic component" is a monomer, macromer, prepolymer, initiator, crosslinker, additive, or polymer that, when mixed with deionized water at 25°C at a concentration of 5 weight percent, gives a clear, single-phase solution. A "hydrophobic component" is a monomer, macromer, prepolymer, initiator, crosslinker, additive, or polymer that is slightly soluble or insoluble in deionized water at 25°C.

[0033] A "macromolecule" is an organic compound having a number average molecular weight greater than 1500, and may be reactive or non-reactive.

[0034] A "macromonomer" or "macromer" is a macromolecule having one group capable of undergoing chain-growth polymerization, particularly free-radical polymerization, thereby creating repeat units within the chemical structure of a target macromolecule. Generally, the chemical structure of a macromer differs from that of a target macromolecule; i.e., the repeat units of the pendant group of the macromer differ from the repeat units of the target macromolecule or its backbone. The only differences between a monomer and a macromer are the chemical structure of the pendant group, the molecular weight, and the molecular weight distribution. Consequently, and as used herein, patent literature sometimes defines a monomer as a polymerizable compound having a relatively low molecular weight of about 1,500 daltons or less, which essentially includes some macromers. Specifically, monomethacryloxypropyl-terminated, mono-n-butyl-terminated polydimethylsiloxane (molecular weight = 500-1500 g / mol) (mPDMS) and mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether-terminated, mono-n-butyl-terminated polydimethylsiloxane (molecular weight = 500-1500 g / mol) (OH-mPDMS) may be referred to as monomers or macromers. Furthermore, patent literature sometimes defines macromers as having one or more polymerizable groups, essentially expanding the general definition of macromer to include prepolymers. Consequently, and as used herein, difunctional and multifunctional macromers, prepolymers, and crosslinkers may be used interchangeably.

[0035] A "silicone-containing component" is a monomer, macromer, prepolymer, crosslinker, initiator, additive, or polymer in a reactive mixture that has at least one silicon-oxygen bond, usually in the form of a siloxy group, a siloxane group, a carbosiloxane group, and mixtures thereof.

[0036] Examples of silicone-containing components useful in the present invention are disclosed in U.S. Pat. Nos. 3,808,178, 4,120,570, 4,136,250, 4,153,641, 4,740,533, 5,034,461, 5,070,215, 5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,760,100, 5,849,811, 5,96 No. 2,548, No. 5,965,631, No. 5,998,498, No. 6,367,929, No. 6,822,016, No. 6,943,203, No. 6,951,894, No. 7,052,131, No. No. 7,247,692, No. 7,396,890, No. 7,461,937, No. 7,468,398, No. 7,538,146, No. 7,553,880, No. 7,572,841, No. 7,666,921 , No. 7,691,916, No. 7,786,185, No. 7,825,170, No. 7,915,323, No. 7,994,356, No. 8,022,158, No. 8,163,206, No. 8,273, No. 802, No. 8,399,538, No. 8,415,404, No. 8,420,711, No. 8,450,387, No. 8,487,058, No. 8,568,626, No. 8,937,110, No. 8,9 37,111, 8,940,812, 8,980,972, 9,056,878, 9,125,808, 9,140,825, 9,156,934, 9,170,349, 9,217,813, 9,244,196, 9,244,197, 9,260,544, 9,297,928, 9,297,929, and European Patent No. 080539. These patents are incorporated herein by reference in their entirety.

[0037] A "polymer" is a target macromolecule made up of repeating units of the monomers used during polymerization.

[0038] A "homopolymer" is a polymer made from one monomer; a "copolymer" is a polymer made from two or more monomers; and a "terpolymer" is a polymer made from three monomers. A "block copolymer" consists of compositionally distinct blocks or segments. A diblock copolymer has two blocks. A triblock copolymer has three blocks. A "comb or graft copolymer" is made from at least one macromer.

[0039] A "repeating unit" is the smallest group of atoms in a polymer that corresponds to the polymerization of a particular monomer or macromer.

[0040] An "initiator" is a molecule that can decompose into radicals that can subsequently react with monomers to initiate a free-radical polymerization reaction. Thermal initiators decompose at a specific rate depending on the temperature, and typical examples are azo compounds such as 1,1'-azobisisobutyronitrile and 4,4'-azobis(4-cyanovaleric acid); peroxides such as benzoyl peroxide, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl peroxybenzoate, dicumyl peroxide, and lauroyl peroxide; peracids such as peracetic acid and potassium persulfate; and various redox systems. Photoinitiators decompose by a photochemical process, and typical examples are derivatives of benzil, benzoin, acetophenone, benzophenone, camphorquinone, and mixtures thereof, as well as various monoacyl and bisacylphosphine oxides and combinations thereof.

[0041] A "crosslinker" is a di- or polyfunctional monomer or macromer that can undergo free radical polymerization at two or more positions on the molecule, thereby creating branch points and polymer networks. Common examples are ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, trimethylolpropane trimethacrylate, methylene bisacrylamide, triallyl cyanurate, etc.

[0042] A "prepolymer" is a reaction product of monomers that contain remaining polymerizable groups that can undergo further reaction to form a polymer.

[0043] A "polymer network" is a cross-linked macromolecule that can swell but cannot be dissolved in a solvent. A "hydrogel" is a polymer network that swells in water or an aqueous solution, typically absorbing at least 10 weight percent of water. A "silicone hydrogel" is a hydrogel made from at least one silicone-containing component together with at least one hydrophilic component. The hydrophilic component may also include a non-reactive polymer.

[0044] "Conventional hydrogel" refers to a polymer network made from components that do not have any siloxy, siloxane, or carbosiloxane groups. Conventional hydrogels are prepared from reactive mixtures that include hydrophilic monomers. Examples include 2-hydroxyethyl methacrylate ("HEMA"), N-vinylpyrrolidone ("NVP"), N,N-dimethylacrylamide ("DMA"), or vinyl acetate. U.S. Patent Nos. 4,436,887, 4,495,313, 4,889,664, 5,006,622, 5,039459, 5,236,969, 5,270,418, 5,298,533, 5,824,719, 6,420,453, 6,423,761, 6,767,979, 7,934,830, 8,138,290, and 8,389,597 disclose the formation of conventional hydrogels. Commercially available conventional hydrogels include, but are not limited to, etafilcon, genfilcon, hilafilcon, lenefilcon, nesofilcon, omafilcon, polymacon, and vifilcon, including all variations thereof.

[0045] "Silicone hydrogel" refers to a polymer network made from at least one hydrophilic component and at least one silicone-containing component. Examples of silicone hydrogels include acquafilcon, asmofilcon, balafilcon, comfilcon, delefilcon, enfilcon, falcon, fanfilcon, formofilcon, galyfilcon, lotrafilcon, and the like. on, narafilcon, riofilcon, samfilcon, senofilcon, somofilcon, and stenfilcon (including all variations thereof), and the compounds described in U.S. Patent Nos. 4,659,782, 4,659,783, 5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,998,499, and the like. No. 8, No. 6,087,415, No. 5,760,100, No. 5,776,999, No. 5,789,461, No. 5 , No. 849,811, No. 5,965,631, No. 6,367,929, No. 6,822,016, No. 6,867,2 No. 45, No. 6,943,203, No. 7,247,692, No. 7,249,848, No. 7,553,880, No. No. 7,666,921, No. 7,786,185, No. 7,956,131, No. 8,022,158, No. 8,273, 802, 8,399,538, 8,470,906, 8,450,387, 8,487,058, No. 8,507,577, No. 8,637,621, No. 8,703,891, No. 8,937,110, No. 8,937 , No. 111, No. 8,940,812, No. 9,056,878, No. 9,057,821, No. 9,125,808, No. 9,140,825, No. 9156,934, No. 9,170,349, No. 9,244,196, No. 9,244,197, 9,260,544, 9,297,928, 9,297,929, as well as silicone hydrogels such as those prepared in WO 03 / 22321, WO 2008 / 061992, and U.S. Patent Application Publication No. 2010 / 0048847, all of which are incorporated herein by reference in their entireties.

[0046] An "interpenetrating polymer network" comprises two or more networks that are at least partially entangled on a molecular scale, but are not covalently bonded to each other and cannot be separated without interlocking chemical bonds. A "semi-penetrating polymer network" comprises one or more networks and one or more polymers characterized by some intermixing at the molecular level between at least one network and at least one polymer. A mixture of different polymers is a "polymer blend." Although a semi-penetrating network is technically a polymer blend, in some cases the polymers are entangled so that they cannot be easily removed.

[0047] The terms "reactive mixture" and "reactive monomer mixture" refer to a mixture of components (both reactive and non-reactive) that, when mixed together and subjected to polymerization conditions, form conventional or inventive silicone hydrogels, and from which contact lenses are made. The reactive monomer mixture may include reactive components such as monomers, macromers, prepolymers, crosslinkers, and initiators; additives such as wetting agents, release agents, polymers, dyes; light-absorbing compounds, e.g., UV absorbers, pigments, dyes, and photochromic compounds (any of which may be reactive or non-reactive but can be retained in the resulting biomedical device); pharmaceutical and nutraceutical compounds; and optional diluents. It will be understood that various additives may be added depending on the biomedical device being fabricated and its intended use. The concentrations of the components of the reactive mixture are expressed as weight percentages of all components in the reactive mixture, excluding the diluent. If a diluent is used, their concentration is expressed as weight percentages based on the amount of all components and diluent in the reactive mixture.

[0048] A "reactive component" is a component of the reactive mixture that becomes part of the chemical structure of the polymer network of the resulting hydrogel through covalent bonding, hydrogen bonding, electrostatic interactions, formation of an interpenetrating polymer network, or any other means.

[0049] The term "silicone hydrogel contact lenses" refers to hydrogel contact lenses that include at least one silicone-containing component. Silicone hydrogel contact lenses generally have increased oxygen permeability compared to traditional hydrogels. Silicone hydrogel contact lenses utilize both their water content and polymer content to deliver oxygen to the eye.

[0050] The term "multifunctional" refers to a component having two or more polymerizable groups. The term "monofunctional" refers to a component having one polymerizable group.

[0051] The terms "halogen" or "halo" refer to fluorine, chlorine, bromine, and iodine.

[0052] As used herein, the term "alkyl" refers to an unsubstituted or substituted straight- or branched-chain alkyl group containing the indicated number of carbon atoms. If no number is specified, the alkyl (optionally including any substituents on the alkyl) can contain 1 to 16 carbon atoms. Preferably, the alkyl group contains 1 to 10 carbon atoms, alternatively 1 to 7 carbon atoms, or alternatively 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-, and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. Examples of substituents on alkyl include one, two, or three groups independently selected from hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halogen, phenyl, benzyl, and combinations thereof. "Alkylene" means a divalent alkyl group such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, and -CH2CH2CH2CH2-.

[0053] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogen atoms, where each halogen is independently F, Cl, Br, or I. A preferred halogen is F. Preferred haloalkyl groups contain 1 to 6 carbons, more preferably 1 to 4 carbons, and even more preferably 1 to 2 carbons. "Haloalkyl" includes perhaloalkyl groups such as -CF3- or -CF2CF3-. "Haloalkylene" refers to a divalent haloalkyl group, such as -CH2CF2-.

[0054] "Cycloalkyl" refers to an unsubstituted or substituted cyclic hydrocarbon containing the specified number of ring carbon atoms. If no number is specified, the cycloalkyl can contain 3 to 12 ring carbon atoms. Preferred are C3-C8 cycloalkyl groups, C3-C7 cycloalkyl, more preferably C4-C7 cycloalkyl, and even more preferably C5-C6 cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of substituents on cycloalkyl include one, two, or three groups independently selected from alkyl, hydroxy, amino, amido, oxa, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, and combinations thereof. "Cycloalkylene" refers to a divalent cycloalkyl group such as 1,2-cyclohexylene, 1,3-cyclohexylene, or 1,4-cyclohexylene.

[0055] "Heterocycloalkyl" refers to a cycloalkyl ring or ring system, as defined above, in which at least one ring carbon is replaced with a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring is optionally fused or otherwise attached to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings and / or phenyl rings. Preferred heterocycloalkyl groups have 5 to 7 members. More preferred heterocycloalkyl groups have 5 or 6 members. Heterocycloalkylene refers to a divalent heterocycloalkyl group.

[0056] "Aryl" refers to an unsubstituted or substituted aromatic hydrocarbon ring system containing at least one aromatic ring. The aryl group contains the specified number of ring carbon atoms. If no number is specified, the aryl may contain 6 to 14 ring carbon atoms. The aromatic ring may optionally be fused to or otherwise attached to other aromatic or non-aromatic hydrocarbon rings. Examples of aryl groups include phenyl, naphthyl, and biphenyl. Preferred examples of aryl groups include phenyl. Examples of substituents on aryl groups include one, two, or three groups independently selected from alkyl, hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, and combinations thereof. "Arylene" refers to a divalent aryl group, such as 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene.

[0057] "Heteroaryl" refers to an aryl ring or ring system, as defined above, in which at least one ring carbon atom is replaced with a heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise bonded to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. Examples of heteroaryl groups include pyridyl, furyl, and thienyl. "Heteroarylene" refers to a divalent heteroaryl group.

[0058] "Alkoxy" refers to an alkyl group attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, and isopropoxy. "Aryloxy" refers to an aryl group attached to the parent molecular moiety through an oxygen bridge. Examples include phenoxy. "Cyclic alkoxy" refers to a cycloalkyl group attached to the parent moiety through an oxygen bridge.

[0059] "Alkylamine" refers to an alkyl group attached to the parent molecular moiety through an -NH bridge. Alkyleneamine refers to a divalent alkylamine group, such as -CH2CH2NH-.

[0060] "Siloxanyl" refers to a structure having at least one Si-O-Si bond. Thus, for example, a siloxanyl group refers to a group having at least one Si-O-Si group (i.e., a siloxane group), and a siloxanyl compound refers to a compound having at least one Si-O-Si group. "Siloxanyl" refers to monomers (e.g., Si-O-Si) as well as oligomeric / polymeric structures (e.g., -[Si-O] n -wherein n is 2 or 3 or greater. Each silicon atom in the siloxanyl group is independently selected to complete their valence. A group (where R A is as defined in options (b) to (i) of Formula A).

[0061] "Silyl" refers to a structure of formula R3Si-, and "siloxy" refers to a structure of formula R3Si-O-, where each R in silyl or siloxy is independently selected from trimethylsiloxy, C1-C8 alkyl (preferably C1-C3 alkyl, more preferably ethyl or methyl), and C3-C8 cycloalkyl.

[0062] "Alkyleneoxy" refers to a group having the general formula -(alkylene-O-) p -or -(O-alkylene) p" refers to the group -, where alkylene is as defined above, p is 1 to 200, or 1 to 100, or 1 to 50, or 1 to 25, or 1 to 20, or 1 to 10, and each alkylene is independently optionally substituted with one or more groups independently selected from hydroxyl, halo (e.g., fluoro), amino, amido, ether, carbonyl, carboxyl, and combinations thereof. When p is greater than 1, each alkylene may be the same or different, and the alkyleneoxy may be in a block or random configuration. When alkyleneoxy forms a terminal group in a molecule, the terminus of the alkyleneoxy may be, for example, hydroxy or alkoxy (e.g., HO-[CHCHO] p - or CHO-[CHCHO] p Examples of alkyleneoxy include polymethyleneoxy, polyethyleneoxy, polypropyleneoxy, polybutyleneoxy, and poly(ethyleneoxy-co-propyleneoxy).

[0063] "Oxaalkylene" refers to an alkylene group as defined above in which one or more non-adjacent CH groups are replaced with an oxygen atom, such as -CHCHOCH(CH)CH-. "Thiaalkylene" refers to an alkylene group as defined above in which one or more non-adjacent CH groups are replaced with a sulfur atom, such as -CHCHSCH(CH)CH-.

[0064] The term "linking group" refers to a moiety that connects a polymerizable group to a parent molecule. The linking group may be any moiety that does not unnecessarily interfere with the polymerization of the compound of which it is a part. For example, the linking group may be a bond or may include one or more alkylene, haloalkylene, amide, amine, alkyleneamine, carbamate, carboxylate (-CO-), arylene, heteroarylene, cycloalkylene, heterocycloalkylene, alkyleneoxy, oxaalkylene, thiaalkylene, haloalkyleneoxy (alkyleneoxy substituted with one or more halo groups (e.g., -OCF-, -OCFCF-, -OCFCH-), siloxanyl, alkylenesiloxanyl, or combinations thereof. The linking group may be optionally substituted with one or more substituents. Suitable linking groups include, but are not limited to, alkylene, haloalkylene, cycloalkylene, heterocycloalkylene, alkyleneoxy, oxaalkylene, thiaalkylene, haloalkyleneoxy (alkyleneoxy substituted with one or more halo groups (e.g., -OCF-, -OCFCF-, -OCFCH-), siloxanyl, alkylenesiloxanyl, or combinations thereof. The linking group may be optionally substituted with one or more substituents. Suitable substituents may include those independently selected from alkyl, halo (e.g., fluoro), hydroxyl, HO-alkyleneoxy, CHO-alkyleneoxy, siloxanyl, siloxy, siloxy-alkyleneoxy-, siloxy-alkylene-alkyleneoxy- (two or more alkyleneoxy groups may be present, and each methylene in the alkylene and alkyleneoxy is independently optionally substituted with hydroxyl), ether, amine, carbonyl, carbamate, and combinations thereof. The linking group may also be substituted with a polymerizable group (in addition to the polymerizable group to which it is connected), such as (meth)acrylate.

[0065] Preferred linking groups include C1-C8 alkylene (preferably C2-C6 alkylene) and C1-C8 oxaalkylene (preferably C2-C6 oxaalkylene), each of which is optionally substituted with one or two groups independently selected from hydroxyl and siloxy. Preferred linking groups also include carboxylate, amide, C1-C8 alkylene-carboxylate-C1-C8 alkylene, or C1-C8 alkylene-amide C1-C8 alkylene.

[0066] When the linking group is composed of a combination of moieties as described above (e.g., alkylene and cycloalkylene), the moieties may be present in any order. For example, in Formula E below, if L is shown to be -alkylene-cycloalkylene-, then Rg-L may be either Rg-alkylene-cycloalkylene- or Rg-cycloalkylene-alkylene-. Regardless, the listed order represents the preferred order in which the moieties appear in the compound, starting from the terminal polymerizable group (Rg) to which the linking group is attached. For example, in Formula E, L and L 2 and -L are preferably Rg-alkylene-cycloalkylene-, and -L 2 -Rg is preferably -cycloalkylene-alkylene-Rg.

[0067] As used herein, "nanoparticle" refers to a microparticle having at least one dimension less than 100 nm. In some cases, nanoparticles may have at least one dimension less than 50 nm. As used herein, "plasmonic nanoparticle" refers to a metal nanoparticle with a strong absorption (and scattering) spectrum that can be tuned by varying the shape, composition, or medium surrounding the particle surface. This term will be understood to include all plasmonic nanoparticles of various shapes that produce surface plasmon absorption and scattering spectra in the blue region of the electromagnetic spectrum (e.g., 400 nm to 500 nm).

[0068] As used herein, "surface plasmon" or "surface plasmon resonance" refers to the resonant oscillation of the oscillating electric field of a light beam propagating near a colloidal nanoparticle, which interacts with free electrons and thus causes oscillations of the electronic charge in resonance with the frequency of visible light.

[0069] As used herein, "optical indicator" means any desired substance that can be reduced and, upon reduction, undergoes a visually detectable and / or machine-detectable change, such as color, fluorescence, luminescence, transmittance, polarization, and / or refractive index. Examples of observable changes include a change in absorption wavelength (e.g., a change in color), a change in emission wavelength, a change in fluorescence lifetime, and a change in fluorescence quantum yield. A change in fluorescence quantum yield can include a decrease in fluorescence intensity (referred to as "quenching") or an increase in fluorescence intensity.

[0070] As used herein, the phrase "visible indicia" refers to an optical indicia that undergoes a visually detectable and / or machine-detectable change in optical properties within the visible region of the electromagnetic spectrum (e.g., at wavelengths between 350 nm and 750 nm).

[0071] As used herein, the term "biocompatible" is intended to describe a material that does not induce substantial adverse reactions in vivo. In certain embodiments, a material is "biocompatible" if it is not toxic to cells. In certain embodiments, materials are "biocompatible" if their addition to cells in vitro results in 20% or less cell death, and / or their administration in vivo does not induce inflammation or other such side effects.

[0072] As used herein, the term "static concentration" refers to a concentration of a trigger that can vary from about 1% to about 10%. For example, the static concentration can vary by + / - 10%, + / - 5%, + / - 2%, or + / - 1%.

[0073] Unless otherwise stated, ratios, percentages, parts, etc. are by weight.

[0074] Unless otherwise stated, a numerical range such as, for example, "2 to 10" is inclusive of the numbers defining the range (eg, 2 and 10).

[0075] system Provided herein are systems and methods that can be used to indicate the amount of time that has elapsed since the occurrence of a trigger event. More specifically, the present application relates to systems and methods that can be used to visually indicate, for example, the amount of time that has elapsed since an article was removed from a package, the amount of time that has elapsed since an article or composition was prepared, and / or the amount of time that an article is in use.

[0076] The system may include an indicator disposed on or within the article. The article may be enclosed in a sealable container of the package. The system may further include a trigger disposed within the container and in contact with the indicator. The indicator may respond to a change in the concentration of the trigger in contact with the indicator. As described in more detail below, the indicator may include a nanoparticle, a chromophore, or a fluorophore, or a combination thereof. The trigger may include a capping agent, a dispersing agent, a quencher, a second fluorophore, or a combination thereof.

[0077] The trigger may be present in the sealable container at a static concentration. For example, in some embodiments, the concentration of the trigger may vary by less than + / - 10% (e.g., less than + / - 5%, less than + / - 2%, or less than + / - 1%) from the time the article is enclosed in the sealable container to the time the article is removed from the sealable container.

[0078] Removal of the article from the sealable container can induce a change in the concentration of the trigger in contact with the indicator. The change in the concentration of the trigger can induce an observable change in the indicator. For example, in some embodiments, the indicator can be an optical indicator (e.g., a visible indicator) in which the observable change includes a change in color of the indicator. In such cases, the observable change can be a change in color from a first color within the visible spectrum to a second color within the visible spectrum, a change in color from a first color outside the visible spectrum to a second color within the visible spectrum, or a change in color from a first color within the visible spectrum to a second color outside the visible spectrum. The observable change (e.g., color change) can indicate that a predetermined period of time has elapsed since the article was removed from the container. In some embodiments, the predetermined period of time can be between 30 minutes and 30 days, e.g., between 1 hour and 30 days. For example, the predetermined period of time can be between 24 hours and 30 days, between 1 hour and 15 days, or between 24 hours and 15 days.

[0079] Importantly, the observable change can be discrete, such that substantially all of the observable change (e.g., color change) occurs within a predetermined period of time. For example, substantially no observable change can occur before the predetermined period of time. The observable change can then occur within a relatively short period of time at and after the predetermined period of time. For example, substantially all of the observable change can occur within 48 hours (e.g., within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 4 hours, within 3 hours, within 2 hours, within 1 hour, or within 30 minutes) of the predetermined period of time.

[0080] In some embodiments, a change in the concentration of the trigger can induce two or more observable changes in the indicator to indicate that two or more predetermined periods have elapsed since the item was removed from the container. In some embodiments, the first predetermined period can be between 10 minutes and two weeks, and the second predetermined period can be between 30 minutes and 30 days, e.g., between 1 hour and 30 days. For example, the first predetermined period can be between 15 minutes and two weeks, between 30 minutes and two weeks, between 1 hour and two weeks, between 1 hour and 24 hours, between 1 hour and one week, between 30 minutes and one week, or between 10 minutes and 24 hours, and the second predetermined period can be between 1 hour and 30 days, between 24 hours and 30 days, between 1 hour and 15 days, or between 24 hours and 15 days.

[0081] Nanoparticle Indicators In some embodiments, the indicator may comprise a population of nanoparticles stabilized by a capping agent, in which the trigger comprises a solution containing the capping agent in contact with the indicator.

[0082] The concentration of the capping agent in the trigger can comprise an equilibrium concentration of the capping agent. When the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the capping agent dissociates from the nanoparticles, thereby inducing aggregation of the population of nanoparticles. This aggregation results in a color change.

[0083] The capping agent dissociates from the nanoparticles at a rate selected (by selecting an appropriate capping agent) such that the color change indicates that a predetermined period of time has elapsed since the article was removed from the container. In some embodiments, the predetermined period of time is between 1 hour and 30 days. For example, the predetermined period of time can be between 24 hours and 30 days, between 1 hour and 15 days, or between 24 hours and 15 days. The color change can be observed (e.g., visually and / or spectroscopically) by a user of the article to determine whether a predetermined period of time has elapsed since the article was removed from the container.

[0084] If desired, multiple populations of nanoparticles stabilized by capping agents can be combined in a single indicator to provide multiple observable indicators of the time elapsed since the article was removed from its container. For example, in some embodiments, the indicator can include a first population of nanoparticles stabilized by a first capping agent and a second population of nanoparticles stabilized by a second capping agent. The trigger can include a solution containing a first capping agent and a second capping agent in contact with the indicator. In these embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the first capping agent dissociates from the first population of nanoparticles at a different rate (e.g., a faster rate) than the second capping agent dissociates from the second population of nanoparticles. When the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the first capping agent can dissociate from the first population of nanoparticles, thereby inducing aggregation of the first population of nanoparticles and producing a first color change. The second capping agent can then dissociate from the second population of nanoparticles, thereby inducing aggregation of the second population of nanoparticles and producing a second color change.

[0085] The first capping agent can dissociate from the first population of nanoparticles at a first rate selected (by selecting an appropriate capping agent) so that a first color change indicates that a first predetermined time period has elapsed since the item was removed from the container. Similarly, the second capping agent can dissociate from the second population of nanoparticles at a second rate selected (by selecting an appropriate capping agent) so that a second color change indicates that a second predetermined time period has elapsed since the item was removed from the container. In some embodiments, the first predetermined time period can be 10 minutes to 2 weeks, 15 minutes to 2 weeks, 30 minutes to 2 weeks, 1 hour to 2 weeks, 1 hour to 24 hours, 1 hour to 1 week, 30 minutes to 1 week, or 10 minutes to 24 hours, and the second predetermined time period can be 1 hour to 30 days, 24 hours to 30 days, 1 hour to 15 days, or 24 hours to 15 days.

[0086] In some embodiments, the nanoparticles can comprise plasmonic nanoparticles. The plasmonic nanoparticles can comprise any suitable noble metal (e.g., gold, silver, platinum, palladium, or any combination thereof). In some embodiments, the nanoparticles can comprise gold. In particular embodiments, the nanoparticles can be comprised of gold. In some embodiments, the nanoparticles can comprise silver. In particular embodiments, the nanoparticles can be comprised of silver.

[0087] The size and shape of the nanoparticles can be varied to tailor their optical properties. For example, by varying the size and shape of the nanoparticles, the absorption of the nanoparticles can be tuned over a wide range of wavelengths. The nanoparticles can have any suitable shape, such as cages, cones, cylinders, cubes, cuboids, hexagons, icosahedrons, octahedrons, plates, prisms, pyramids, rings, rods, shells, spheres, stars, tetrahedrons, etc.

[0088] In some embodiments, the nanoparticles can have a polyhedral shape. For example, the nanoparticles can have a cubic, octahedral, decahedral, cuboctahedral, tetrahedral, rhombic dodecahedral, truncated bicubic prism, or truncated ditetrahedral shape. In other embodiments, the nanoparticles can have a spherical shape. In other embodiments, the nanoparticles can include rods.

[0089] In some cases, the population of nanoparticles can have a homogeneous particle shape. In these embodiments, substantially all of the nanoparticles (e.g., at least 90%, at least 95%, or at least 98% of the nanoparticles) can have the same particle shape. In other cases, the population of nanoparticles can include a mixture of particle shapes (e.g., a mixture of two, three, four, five, six, seven, or more different particle shapes within the population of nanoparticles). For example, in some examples, the nanoparticles include a first population of nanoparticles having a first shape and a second population of nanoparticles having a second shape.

[0090] A population of nanoparticles can have an average particle size. "Average particle size" and "mean particle size" are used interchangeably herein and generally refer to the statistical average particle size of nanoparticles in a population of nanoparticles. For nanoparticles having a substantially spherical shape, the diameter of the nanoparticle can refer, for example, to the hydrodynamic diameter. As used herein, the hydrodynamic diameter of a particle can refer to the largest linear distance between two points on the surface of the particle. For nanoparticle cores having a non-spherical shape, the diameter of the nanoparticle can refer, for example, to the smallest cross-sectional dimension of the nanoparticle (i.e., the smallest linear distance passing through the center of the nanoparticle and intersecting two points on the surface of the particle). Average particle size can be measured using methods known in the art, such as scanning electron microscopy, transmission electron microscopy, and / or dynamic light scattering evaluation.

[0091] In some embodiments, the nanoparticles can have an average particle size of at least 5 nm (e.g., at least 10 nm, at least 15 nm, at least 20 nm, at least 25 nm, at least 30 nm, at least 35 nm, at least 40 nm, at least 45 nm, at least 50 nm, at least 55 nm, at least 60 nm, at least 65 nm, at least 70 nm, at least 75 nm, at least 80 nm, at least 85 nm, at least 90 nm, or at least 95 nm) as measured by transmission electron microscopy (TEM). In some embodiments, the nanoparticles can have an average particle size of 100 nm or less (e.g., 95 nm or less, 90 nm or less, 85 nm or less, 80 nm or less, 75 nm or less, 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, or 10 nm or less) as measured by transmission electron microscopy (TEM.

[0092] The nanoparticles can have an average particle size ranging from any of the minimum values ​​described above to any of the maximum values ​​described above. For example, in some embodiments, the nanoparticles can have an average particle size of 5 nm to 100 nm (e.g., 20 nm to 60 nm) as measured by transmission electron microscopy (TEM).

[0093] In some cases, nanoparticles may have a monodisperse particle size distribution. As used herein, "monodisperse" and "homogeneous size distribution" generally describe a population of particles in which all of the particles are the same or approximately the same size. As used herein, monodisperse refers to a particle distribution in which 80% of the distribution (e.g., 85% of the distribution, 90% of the distribution, or 95% of the distribution) is within 25% of the average particle size (e.g., within 20% of the average particle size, within 15% of the average particle size, within 10% of the average particle size, or within 5% of the average particle size). In other cases, nanoparticles may have a polydisperse or heterogeneous particle size distribution.

[0094] In some embodiments, the nanoparticles can exhibit a maximum absorption value of at least 450 nm (e.g., at least 475 nm, at least 500 nm, at least 525 nm, at least 550 nm, at least 575 nm, at least 600 nm, at least 625 nm, at least 650 nm, at least 675 nm, at least 700 nm, or at least 725 nm). In some embodiments, the nanoparticles can exhibit a maximum absorption value of 750 nm or less (e.g., 725 nm or less, 700 nm or less, 675 nm or less, 650 nm or less, 625 nm or less, 600 nm or less, 575 nm or less, 550 nm or less, 525 nm or less, 500 nm or less, or 475 nm or less).

[0095] The nanoparticles can exhibit a maximum absorption value ranging from any of the above minimum values ​​to any of the above maximum values. For example, in some embodiments, the nanoparticles can exhibit a maximum absorption value between 450 nm and 750 nm (e.g., between 450 nm and 500 nm, between 500 nm and 550 nm, between 550 nm and 600 nm, between 600 nm and 650 nm, between 650 nm and 700 nm, or between 700 nm and 750 nm).

[0096] In some embodiments, the nanoparticles can exhibit an absorption spectrum with a full width at full width half maximum of at least 20 nm (e.g., at least 25 nm, at least 30 nm, at least 35 nm, at least 40 nm, at least 45 nm, at least 50 nm, at least 55 nm, at least 60 nm, at least 65 nm, or at least 70 nm). In some embodiments, the nanoparticles can exhibit an absorption spectrum with a full width at full width half maximum of 75 nm or less (e.g., 70 nm or less, 65 nm or less, 60 nm or less, 55 nm or less, 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, or 25 nm or less).

[0097] The nanoparticles can exhibit an absorption spectrum having a full width at half maximum ranging from any of the minimum values ​​described above to any of the maximum values ​​described above. For example, in some embodiments, the core-shell particles can exhibit an absorption spectrum having a full width at half maximum of 20 nm to 75 nm.

[0098] The capping agent can include any suitable agent that stabilizes the nanoparticles, thereby minimizing aggregation of the nanoparticles when the capping agent is associated with the nanoparticles. The capping agent can be non-covalently (ionically) associated with the nanoparticles.

[0099] In some embodiments, the capping agent may be biocompatible, which is particularly preferred in embodiments where the article is intended to be in contact with living organisms.

[0100] Suitable examples of capping agent include, for example, surfactant, polymer, and their combination.Representative examples of capping agent include gelatin, casein, lecithin (phosphatide), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example, macrogol ether such as cetomacrogol 1000), polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (for example, commercially available Tweens), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these capping agents are pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0101] Specific examples of capping agents include polyvinylpyrrolidone, tyloxapol, poloxamers (such as Pluronic™ F68 and F108) which are block copolymers of ethylene oxide and propylene oxide, poloxamines (such as Tetronic™ 908) (also known as Poloxamine 908) which are tetrafunctional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkyl esters of sodium sulfosuccinate (such as Aerosol OT™) which are dioctyl esters of sodium sulfosuccinate (available from American Cyanimid), Duponol™ P (which is sodium lauryl sulfate) (available from DuPont), Triton™ X-200 (which is an alkylaryl polyether sulfonate) (available from Rohm and Haas), Tween 80, which is a polyoxyethylene sorbitan fatty acid ester (available from ICI Specialty Chemicals), and Carbowax™ 3350 and 934, which are polyethylene glycols available from Union Carbide. Other useful capping agents include decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, N-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, and the like.

[0102] In certain embodiments, the capping agent comprises a surfactant, such as an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof. In some examples, the surfactant may include a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, an alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, a polysorbate, or a combination thereof.

[0103] In certain embodiments, the capping agent comprises a polymer such as polyvinylpyrrolidone, polyvinyl alcohol, a polyalkylene oxide such as polyethylene glycol, a cellulosic polymer, tyloxapol, or a combination thereof.

[0104] In other embodiments, the indicator can be a color retention indicator. The capping agent of the color retention indicator does not diffuse out of the container. The capping agent can be retained in the container by the container having a MWCO lower than the molecular weight of the color retention capping agent. In another embodiment, the capping agent can be strongly associated with the indicator such that there is a significant net diffusion of the capping agent out of the container.

[0105] Fluorophore indicators In other embodiments, the indicator can include a fluorophore in combination with a dispersing agent, and the trigger can include a solution including the dispersing agent in contact with the indicator. In some embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the dispersing agent dissociates from the fluorophore, thereby producing aggregation of the fluorophore and a shift in maximum emission wavelength (e.g., a red shift).

[0106] The dispersing agent can dissociate from the fluorophore at a rate selected so that a change in the fluorescence of the fluorophore indicates that a predetermined period of time has elapsed since the article was removed from the container. The change in fluorescence can include a change in maximum emission wavelength, a change in fluorescence quantum yield, a change in the shape of the emission spectrum, a change in fluorescence lifetime, or a combination thereof.

[0107] In other embodiments, the indicator can include a fluorophore, and the trigger can include a solution including a quencher in contact with the indicator. In some embodiments, when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the quencher can dissociate from the fluorophore, thereby inducing an increase in fluorescence. The quencher can dissociate from the fluorophore at a rate selected so that the increase in fluorescence indicates that a predetermined period of time has elapsed since the article was removed from the container.

[0108] In other embodiments, the indicator can include a first fluorophore, and the trigger can include a solution including a second fluorophore in contact with the indicator. The first fluorophore and the second fluorophore can comprise a fluorescence resonance energy transfer (FRET) pair. The second fluorophore can dissociate from the first fluorophore, thereby generating a change in maximum emission wavelength. The second fluorophore can dissociate from the first fluorophore at a rate selected such that the change in maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container.

[0109] Fluorophores can be selected to have photophysical properties that facilitate observation and / or analysis of the spectroscopic properties of the fluorophore. For example, in certain embodiments, the fluorophore has a fluorescence quantum yield that facilitates observation and / or measurement of the fluorescence of the indicator. In some cases, the fluorophore has a quantum yield in aqueous solution of at least 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, or 0.90.

[0110] In some cases, the fluorophore does not have an emission maximum in a spectral region that substantially overlaps with the autofluorescence of a biological sample. In certain embodiments, the fluorophore has an emission maximum in aqueous solution of 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm, 550 nm, 560 nm, 570 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, or greater than 700 nm. In certain embodiments, the fluorophore has an emission maximum in aqueous solution of 430 nm to 700 nm, more preferably 450 nm to 700 nm, and most preferably 480 nm to 700 nm. In some embodiments, the fluorophore has an emission maximum in aqueous solution between 430 nm and 1200 nm, more preferably between 450 nm and 1200 nm, and most preferably between 480 nm and 1200 nm.

[0111] In preferred embodiments, the fluorophore is selected to have photophysical properties, including a fluorescence quantum yield and an emission maximum, that are observable with the naked eye when the indicator (e.g., an article containing the indicator) is irradiated with UV light. In some embodiments, the fluorophore has a high quantum yield and emits at a long wavelength. In certain embodiments, the fluorophore has an emission maximum greater than 450 nm and a quantum yield greater than 0.10 in aqueous solution.

[0112] A variety of suitable fluorophores can be used as indicators. Fluorophores useful as indicators typically contain extended conjugated paths (e.g., alternating single and double bonds) in which pi electrons are delocalized. Fluorophores can be aromatic, meaning that they contain one or more aromatic rings, or non-aromatic (e.g., linear structure). In a preferred embodiment, fluorophores contain one or more aromatic rings.

[0113] In some embodiments, the fluorophore is an organic or organometallic small molecule. Suitable small molecule fluorophores are known in the art and include xanthene and xanthene derivatives, such as fluorescein or fluorescein derivatives, rhodamine, Oregon Green, eosin, Texas Red, and Cal. Fluor dyes, cyanines and cyanine derivatives such as indocarbocyanines, oxacarbocyanines, thiacarbocyanines, merocyanines, and Quasar dyes; naphthalene derivatives such as dansyl and prodan derivatives and naphthalene derivatives such as naphthalimides and naphthalimide derivatives; coumarin and its derivatives; oxadiazole derivatives such as pyridixazole, nitrobenzoxadiazole, and benzoxadiazole; pyrene derivatives such as cascade blue; oxazine derivatives such as Nile red, Nile blue, cresyl violet, and oxazine 170; acridine derivatives such as proflavine, acridine orange, and acridine yellow; aryl methine derivatives such as auranamine, crystal violet, and malachite green; tetrapyrrole derivatives such as porphyrins, phthalocyanines, and bilirubin; fluorene derivatives; CF® dyes (available from Biotium); BODIPY® (available from Invitrogen); Alexa Fluor® (available from Invitrogen); DyLight Fluor® (Thermo Other suitable fluorophores include, but are not limited to, those described in Lakowicz, JR, "Principles of Fluorescence Spectroscopy," 2004, pp. 111-114, 2004. nd Ed., Plenum Press, New York, 1999.

[0114] Suitable fluorophores can also include macromolecules such as conjugated polymers, hi some embodiments, the fluorophore is a conjugated polymer such as a poly(aryleneethynylene) containing one or more side chains containing reactive functional groups.

[0115] Other suitable fluorophores include any substance that can absorb energy of an appropriate wavelength and emit or transfer the energy. Typical fluorophores include fluorescent dyes, semiconductor nanocrystals, lanthanide chelates, and fluorescent proteins.

[0116] Exemplary fluorescent dyes include fluorescein, 6-FAM, rhodamine, Texas Red, tetramethylrhodamine, carboxyrhodamine, carboxyrhodamine 6G, carboxyrhodol, carboxyrhodamine 110, Cascade Blue, Cascade Yellow, coumarin, Cy2®, Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy-Chrome, phycoerythrin, PerCP (peridinin chlorophyll-a protein), PerCP-Cy5.5, JOE (6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein), NED, ROX (5-(and-6)-carboxy-X-rhodamine), HEX, Lucifer Yellow, Marina Blue, Oregon Green 488, Oregon Green 500, Oregon Green 514, Alexa Fluor® 350, Alexa Fluor® 516, Alexa Fluor® 518 ... Fluor® 430, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 633, Alexa Fluor® 647, Alexa Fluor® 660, Alexa Examples of lanthanide chelates include Fluor® 680, 7-amino-4-methylcoumarin-3 acetic acid, BODIPY® FL, BODIPY® FL-Br2, BODIPY® 530 / 550, BODIPY® 558 / 568, BODIPY® 564 / 570, BODIPY® 576 / 589, BODIPY® 581 / 591, BODIPY® 630 / 650, BODIPY® 650 / 665, BODIPY® R6G, BODIPY® TMR, BODIPY® TR, conjugates thereof, and combinations thereof. Exemplary lanthanide chelates include europium chelates, terbium chelates, and samarium chelates.Representative fluorescent proteins (FPs) include green fluorescent protein (GFP), red fluorescent protein (RFP), yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), dark FPs, large Stokes shift FPs, near-infrared FPs, and infrared FPs.

[0117] A variety of such fluorescent semiconductor nanocrystals (SCNCs) are known in the art, and methods for making and using semiconductor nanocrystals are described in PCT Publication No. 99 / 26299 (inventors Bawendi et al.), published May 27, 1999, U.S. Patent No. 5,990,479, issued November 23, 1999 to Weiss et al., and Bruchez et al., Science 281:2013, 1998. Semiconductor nanocrystals can be obtained with very narrow emission bands with well-defined peak emission wavelengths, allowing many different SCNCs to be used as signaling chromophores in the same assay, optionally in combination with other non-SCNC-type signaling chromophores.

[0118] In some embodiments, suitable fluorophores may be metal chalcogenide quantum dots, graphene quantum dots, carbon dots, graphite oxide, semiconducting (organic) polymer dots, ultrasmall metal nanoparticles (e.g., gold or silver), metal nanoclusters (e.g., gold, silver, copper), fluorescently doped silica nanoparticles, fluorescently doped silica microparticles, fluorophore-functionalized dendrimers, and upconversion nanoparticles, or combinations thereof.

[0119] As noted above, in some examples, the indicator may include a fluorophore in combination with a dispersing agent. The dispersing agent may include any suitable agent that stabilizes the fluorophore such that aggregation of the fluorophore is minimized in the presence of the dispersing agent. In some embodiments, the dispersing agent may be biocompatible. This is particularly preferred in embodiments where the article is intended to be in contact with a living organism.

[0120] Suitable examples of dispersing agent include, for example, surfactant, polymer, and their combination.Representative examples of dispersing agent include gelatin, casein, lecithin (phosphatide), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example, macrogol ether such as cetomacrogol 1000), polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (for example, commercially available Tweens), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these dispersing agents are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0121] Specific examples of dispersing agents include polyvinylpyrrolidone, tyloxapol, poloxamers (such as Pluronic™ F68 and F108) which are block copolymers of ethylene oxide and propylene oxide, poloxamines (such as Tetronic™ 908) (also known as Poloxamine 908) which are tetrafunctional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkyl esters of sodium sulfosuccinate (such as Aerosol OT™) which are dioctyl esters of sodium sulfosuccinate (available from American Cyanimid), Dupont™ P (which is sodium lauryl sulfate) (available from DuPont), Triton™ X-200 (which is an alkylaryl polyether sulfonate) (available from Rohm and Haas), Tween 80, which is a polyoxyethylene sorbitan fatty acid ester (available from ICI Specialty Chemicals), and Carbowax™ 3350 and 934, which are polyethylene glycols available from Union Carbide. Other useful surface modifiers include decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, N-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, and the like.

[0122] In certain embodiments, the dispersing agent comprises a surfactant, such as an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof. In some examples, the dispersing agent may include a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof.

[0123] In certain embodiments, the dispersing agent comprises a polymer such as polyvinylpyrrolidone, polyvinyl alcohol, a polyalkylene oxide such as polyethylene glycol, a cellulosic polymer, tyloxapol, or a combination thereof.

[0124] As noted above, in other examples, the indicator can include a fluorophore and the trigger can include a solution containing a quencher in contact with the indicator. The term "quencher" refers to a substance or portion thereof that can suppress, reduce, or inhibit the detectable fluorescence produced by a fluorophore. A suitable quencher can be selected taking into account the identity of the fluorophore. Suitable examples of quenchers can be selected from 6-carboxy-tetramethyl-rhodamine, 4-(4-dimethylaminophenylazo)benzoic acid (DABYL), tetramethylrhodamine (TAMRA), BHQ-0™, BHQ-1™, BHQ-2™, and BHQ-3™ (each of which is available from Biosearch Technologies, Inc. of Novato, Calif.), QSY-7™, QSY-9™, QSY-21™, and QSY-35™ (each of which is available from Molecular Probes, Inc., etc.), metal nanoparticles (e.g., gold, silver, copper), graphene oxide, iron oxide nanoparticles, metal organic frameworks, carbon nanoparticles, and quantum dots (QDs), or combinations thereof.

[0125] As described above, in other examples, the indicator can include a first fluorophore, and the trigger can include a solution containing a second fluorophore in contact with the indicator. The first and second fluorophores can comprise a FRET pair. In such pairs, the first and second fluorophores are in close proximity, the first fluorophore is excited by an energy source, and a substantial portion of the excited state energy is non-radiatively transferred to the second fluorophore, which non-radiatively dissociates or is emitted at an emission wavelength different from that of the first fluorophore.

[0126] Suitable FRET pairs are known in the art and can include small organic dyes, fluorescent proteins, metal nanoparticles (e.g., gold, silver, copper), graphene oxide, iron oxide nanoparticles, metal-organic frameworks, carbon nanoparticles, and quantum dots (QDs), or combinations thereof. Exemplary FRET pairs include dansyl-rhodamine, naphthalene-pyrene, Green FP-Red FP, Cyan FP-Yellow FP, CdSe / ZnS QDs, or CdSe / ZnS QDs-Red FP.

[0127] Chromophore index In other embodiments, the indicator may include a chromophore in combination with the dispersant. Various chromophores are known in the art. Examples of suitable chromophores include cyanines, merocyanines, phthalocyanines, naphthalocyanines, triphenylmethines, porphyrins, pyrylium dyes, thiapyrylium dyes, squarylium dyes, croconium dyes, azulenium dyes, indoanilines, benzophenoxazinium dyes, benzothiaphenothiazinium dyes, anthraquinones, naphthoquinones, indanthrenes, phthaloylacridones, trisphenoquinones, azo dyes, intramolecular and intermolecular charge transfer dyes and dye complexes, thorones, tetrazines, bis(dithiolene) complexes, bis(benzene-dithiolate) complexes, iodoaniline dyes, bis(S,O-dithiolene) complexes, and the like.

[0128] Examples of chromophores that can be used include xylene cyanol, fluorescein, dansyl, NBD, indocyanine green, DODCI, DTDCI, DOTCI, and DDTCI. Further examples of organic chromophores include, but are not limited to, cyanine dyes, chalcogenopyrylomethine dyes, pyrylium dyes, thiapyrylium dyes, squarylium dyes, croconium dyes, azulenium dyes, merocyanine dyes, indoaniline dyes including Cu and Ni complexes, indanthrene pigments, trisphenoquinone dyes, azo dyes, non-benzenoid aromatic dyes, tetrazine radical dyes, anthraquinone dyes, naphthoquinone dyes, metallated azo dyes including those containing Ni, Co, Fe, and Mn, phthalocyanine dyes, naphthalcyanine dyes, metal phthalocyanines, metal naphthalcyanines, bis(dithiolene) metal complexes, bis(benzodithiolate) metal complexes, bis(S,O-dithiolene) metal complexes, and tris(α-diimine) metal complexes. Representative examples can be found in U.S. Pat. No. 6,051,207, which is incorporated herein in its entirety.

[0129] In some embodiments, the chromophore may include a visible dye. Examples of visible dyes include, but are not limited to, fluorescein dyes, rhodamine dyes, coumarins, azo dyes, anthraquinone dyes, benzodifuranone dyes, polycyclic aromatic carbonyl dyes, indigoid dyes, polymethine dyes, azacarbocyanine dyes, hemicyanine dyes, diazahemicyanine dyes, stryl dyes, diarylcarbonium dyes, triarylcarbonium dyes, phthalocyanine dyes, quinophthalone dyes, triphenodioxazine dyes, formazan dyes, phenothiazine dyes such as methylene blue, azure A, azure B, and / or azure C, oxazine dyes, thiazine dyes, naphtholactam dyes, diazahemicyanine dyes, azopyridone dyes, azobenzene dyes, xanthene dyes, leuco dyes (which can be oxidized to produce dyes whose hue is bathochromically shifted from that of the precursor leuco dye), and any other visible dye known in the art.

[0130] The dispersing agent can include any suitable agent that stabilizes the chromophore such that aggregation of the chromophore is minimized in the presence of the dispersing agent. In some embodiments, the dispersing agent can be biocompatible. This is particularly preferred in embodiments where the article is intended to be in contact with a living organism.

[0131] Suitable examples of dispersing agent include, for example, surfactant, polymer, and their combination.Representative examples of dispersing agent include gelatin, casein, lecithin (phosphatide), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example, macrogol ether such as cetomacrogol 1000), polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (for example, commercially available Tweens), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these dispersing agents are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0132] Specific examples of dispersing agents include polyvinylpyrrolidone, tyloxapol, poloxamers (such as Pluronic™ F68 and F108) which are block copolymers of ethylene oxide and propylene oxide, poloxamines (such as Tetronic™ 908) (also known as Poloxamine 908) which are tetrafunctional block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkyl esters of sodium sulfosuccinate (such as Aerosol OT™) which are dioctyl esters of sodium sulfosuccinate (available from American Cyanimid), Dupont™ P (which is sodium lauryl sulfate) (available from DuPont), Triton™ X-200 (which is an alkylaryl polyether sulfonate) (available from Rohm and Haas), Tween 80, which is a polyoxyethylene sorbitan fatty acid ester (available from ICI Specialty Chemicals), and Carbowax™ 3350 and 934, which are polyethylene glycols available from Union Carbide. Other useful surface modifiers include decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, N-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, and the like.

[0133] In certain embodiments, the dispersing agent comprises a surfactant, such as an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof. In some examples, the dispersing agent may include a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof.

[0134] In certain embodiments, the dispersing agent comprises a polymer such as polyvinylpyrrolidone, polyvinyl alcohol, a polyalkylene oxide such as polyethylene glycol, a cellulosic polymer, tyloxapol, or a combination thereof.

[0135] In some embodiments, the dispersing agent can dissociate from the chromophores and induce aggregation of the chromophores, producing a color change.

[0136] Goods The systems described herein can be applied to a variety of articles to provide a lead time to assess the amount of time that has elapsed since the article was removed from the package, the amount of time that has elapsed since the article or composition was prepared, and / or the amount of time that the article is in use.

[0137] The indicia can be uniformly distributed throughout the article or region of the article. Alternatively, the indicia can be patterned on and / or within the indicia (e.g., in the form of letters, numbers, shapes, logos, etc.) to create an article having areas that include the indicia and other areas that do not. In some embodiments, the indicia can be present in tablets disposed on and / or within the article, as described in more detail below.

[0138] In some embodiments, the article can include a medical device (e.g., a bandage, an orthodontic device, an implantable medical device). In some embodiments, the article can include an ophthalmic device (e.g., a contact lens, a corneal onlay, a corneal inlay, an intraocular lens, an overlay lens, etc.). In certain embodiments, the ophthalmic device can include a contact lens, such as a hard contact lens or a soft contact lens. In these embodiments, the indicator can function as a compliance indicator and visually indicate when a desired period of time has passed since the contact lens was removed from its packaging (and by extension, when the contact lens needs to be replaced).

[0139] In some embodiments, the article can comprise a hydrogel or silicone hydrogel material suitable for use in forming soft contact lenses. Such materials are known in the art and include Group 1—low water (less than 50% HO) non-ionic hydrogel polymers (e.g., tefilcon, tetrafilcon A, clofilcon, herfilcon A, herfilcon B, mafilcon, polymacon, hyoxifilcon B); Group 2—high water (greater than 50% HO) non-ionic hydrogel polymers (e.g., sarfilcon A, lidofilcon A, lidofilcon B, netrafilcon A, hefilcon B, alfafilcon A, omafilcon A, omafilcon B, busulfilcon A, hyoxifilcon A, hyoxifilcon D, nelfilcon A, hilafilcon A, hilafilcon B, acofilcon A, nesofilcon A); Group 3—low water (less than 50% HO) ionic hydrogel polymers (e.g., bufilcon A, deltafilcon B ... Group 4 - High Water (>50% HO) Ionic Hydrogel Polymers (e.g., Bufilcon A, Perfilcon A, Etafilcon A, Focofilcon A, Ocfilcon A, Ocfilcon B, Ocfilcon C, Ocfilcon D, Ocfilcon E, Ocfilcon F, Femfilcon A, Metafilcon A, Metafilcon B, Bilfufilcon A), and Silicone Hydrogel Polymers (e.g., Lotrafilcon A, Lotrafilcon B, Galifilcon A, Senofilcon A, Senofilcon C, Sifilcon A, Confilcon A, Enfilcon A, Balafilcon A, Derefilcon A, Narafilcon B, Narafilcon A, Stenfilcon A, Somofilcon A, Famfilcon A, Samfilcon A, Elastofilcon).

[0140] In some embodiments, the article can comprise a silicone hydrogel. In certain embodiments, the article can comprise a polymer derived from the polymerization of a reactive mixture comprising a hydrophilic monomer, a silicone-containing component, or a combination thereof. Exemplary silicone hydrogel substrates include those described in detail below.

[0141] hydrophilic component Examples of suitable families of hydrophilic monomers include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinyl lactams, N-vinyl amides, N-vinyl imides, N-vinyl ureas, O-vinyl carbamates, O-vinyl carbonates, other hydrophilic vinyl compounds, and mixtures thereof.

[0142] Non-limiting examples of hydrophilic (meth)acrylate and (meth)acrylamide monomers include acrylamide, N-isopropylacrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl(meth)acrylate, 3-hydroxypropyl(meth)acrylate, 2,3-dihydroxypropyl(meth)acrylate, 2-hydroxybutyl(meth)acrylate, 3-hydroxybutyl(meth)acrylate, 4-hydroxybutyl(meth)acrylate, N-(2-hydroxyethyl)(meth)acrylamide, N,N-bis(2-hydroxyethyl)(meth)acrylamide, N-(2-hydroxypropyl)(meth)acrylamide, N,N-bis(2-hydroxypropyl)(meth)acrylamide, N-(3-hydroxypropyl)(meth)acrylamide, N-hydroxypropyl)(meth)acrylamide, N-(2-hydroxybutyl)(meth)acrylamide, N-(3-hydroxybutyl)(meth)acrylamide, N-(4-hydroxybutyl)(meth)acrylamide, 2-aminoethyl(meth)acrylate, 3-aminopropyl(meth)acrylate, 2-aminopropyl(meth)acrylate, N-2-aminoethyl(meth)acrylamide), N-3-aminopropyl(meth)acrylamide, N-2-aminopropyl(meth)acrylamide, N,N-bis-2-aminoethyl(meth)acrylamide, N,N-bis-3-aminopropyl(meth)acrylamide, N,N-bis-2-aminopropyl(meth)acrylamide, glycerol methacrylate, polyethylene glycol monomethacrylate, (meth)acrylic acid, vinyl acetate, acrylonitrile, and mixtures thereof.

[0143] The hydrophilic monomers may also be ionic, such as anionic, cationic, zwitterionic, betaine, and mixtures thereof. Non-limiting examples of such charged monomers include (meth)acrylic acid, N-[(ethenyloxy)carbonyl]-β-alanine (VINAL), 3-acrylamidopropanoic acid (ACA1), 5-acrylamidopropanoic acid (ACA2), 3-acrylamido-3-methylbutanoic acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q salt or METAC), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), 1-propanaminium, N-(2-carboxyethyl)-N,N-dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-, inner salt (CBT), 1-propanaminium, N,N-dimethyl-N-[3-[(1-oxo-2-propen-1-yl)amino]propyl]-3-sulfo-, inner salt (SBT), 3,5-dioxa-8-aza -4-phosphanundec-10-ene-1-aminium, 4-hydroxy-N,N,N-trimethyl-9-oxo-, inner salt, 4-oxide (9CI) (PBT), 2-methacryloyloxyethyl phosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS), and 3-((3-(methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS).

[0144] Non-limiting examples of hydrophilic N-vinyl lactam and N-vinyl amide monomers include N-vinylpyrrolidone (NVP), N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinylacetamide (NVA), N-vinyl-N-methylacetamide (VMA), N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, N-vinylformamide, N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide, N-vinyl ... N-methylpropionamide, N-vinyl-N,N'-dimethylurea, 1-methyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone, N-methyl-3-methylene-2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, 1-N-propyl-3-methylene-2-pyrrolidone, 1-N-propyl-5-methylene-2-pyrrolidone, 1-isopropyl-3-methylene-2-pyrrolidone, 1-isopropyl-5-methylene-2-pyrrolidone, N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, N-vinylformamide, N-vinylisopropylamide, N-vinylcaprolactam, N-vinylimidazole, and mixtures thereof.

[0145] Non-limiting examples of hydrophilic O-vinyl carbamate and O-vinyl carbonate monomers include N-2-hydroxyethyl vinyl carbamate and N-carboxy-β-alanine N-vinyl ester. Further examples of hydrophilic vinyl carbonate or vinyl carbamate monomers are disclosed in U.S. Patent No. 5,070,215. Hydrophilic oxazolone monomers are disclosed in U.S. Patent No. 4,910,277.

[0146] Other hydrophilic vinyl compounds include ethylene glycol vinyl ether (EGVE), di(ethylene glycol) vinyl ether (DEGVE), allyl alcohol, and 2-ethyloxazoline.

[0147] The hydrophilic monomer may also be a macromer or prepolymer of linear or branched poly(ethylene glycol), poly(propylene glycol), or statistical random or block copolymers of ethylene oxide and propylene oxide, having polymerizable moieties such as (meth)acrylate, styrene, vinyl ether, (meth)acrylamide, N-vinylamide, etc. Macromers of these polyethers have one polymerizable group, and prepolymers may have two or more polymerizable groups.

[0148] Preferred hydrophilic monomers of the present invention are DMA, NVP, HEMA, VMA, NVA, and mixtures thereof. Other suitable hydrophilic monomers will be apparent to those skilled in the art.

[0149] Generally, there are no particular limitations regarding the amount of hydrophilic monomer present in the reactive monomer mixture. The amount of hydrophilic monomer can be selected based on the desired properties of the resulting hydrogel, including water content, transparency, wettability, protein uptake, etc. Wettability can be measured by contact angle, with desirable contact angles being less than about 100°, less than about 80°, and less than about 60°. The hydrophilic monomer can be present in an amount ranging from about 0.1 to about 80 weight percent, such as from about 5 to about 65 weight percent and from about 10 to about 45 weight percent, based on the total weight of the reactive components in the reactive monomer mixture.

[0150] Silicone-containing ingredients Suitable silicone-containing components include one or more polymerizable compounds, each independently containing at least one polymerizable group, at least one siloxane group, and one or more linking groups connecting the polymerizable group to the siloxane group. The silicone-containing component may contain, for example, 1 to 220 siloxane repeating units, such as those defined below. The silicone-containing component may also contain at least one fluorine atom.

[0151] The silicone-containing component may comprise one or more polymerizable groups, as defined above, one or more optionally repeating siloxane units, and one or more linking groups connecting the polymerizable groups to the siloxane units. The silicone-containing component may comprise one or more polymerizable groups, one or more optionally repeating siloxane units, and one or more linking groups connecting the polymerizable groups to the siloxane units, which are independently (meth)acrylate, styryl, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, O-vinyl carbamate, O-vinyl carbonate, vinyl groups, or mixtures thereof.

[0152] The silicone-containing component may independently comprise one or more polymerizable groups that are (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinyl amide, styryl, or mixtures of the foregoing, one or more optionally repeating siloxane units, and one or more linking groups connecting the polymerizable groups to the siloxane units.

[0153] The silicone-containing component may independently comprise one or more polymerizable groups that are (meth)acrylate, (meth)acrylamide, or mixtures of the foregoing, one or more optionally repeating siloxane units, and one or more linking groups connecting the polymerizable groups to the siloxane units.

[0154] Formula A. The silicone-containing component may include one or more polymerizable compounds of Formula A:

[0155] [ka] During the ceremony, At least one R A is the formula R g -L- group, where R g is a polymerizable group, L is a linking group, and the remaining R A are each independently (a)R g -L-, (b) C1-C optionally substituted with one or more hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof. 16 Alkyl, (c) C3-C optionally substituted with one or more alkyl, hydroxy, amino, amido, oxa, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof. 12 cycloalkyl, (d) C6-C optionally substituted with one or more alkyl, hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halo, phenyl, benzyl, or combinations thereof. 14 aryl groups, (e) halo, (f) alkoxy, cyclic alkoxy, or aryloxy; (g) siloxy, (h) alkyleneoxy-alkyl or alkoxy-alkyleneoxy-alkyl, such as polyethyleneoxyalkyl, polypropyleneoxyalkyl, or poly(ethyleneoxy-co-propyleneoxyalkyl); or (i) a monovalent siloxane chain comprising 1 to 100 siloxane repeat units optionally substituted with alkyl, alkoxy, hydroxy, amino, oxa, carboxy, alkylcarboxy, alkoxy, amido, carbamate, halo, or combinations thereof; n is 0 to 500, or 0 to 200, or 0 to 100, or 0 to 20. When n is other than 0, it is understood that n is a distribution having a mode equivalent to the indicated value. When n is 2 or more, the SiO units may be the same or different R A may carry substituents, different R A When substituents are present, the n groups may be in a random or block configuration.

[0156] In formula A, three R A may each contain a polymerizable group, alternatively two R A may each contain a polymerizable group, or alternatively one R A may contain a polymerizable group.

[0157] Formula B. The silicone-containing component of Formula A may be a monofunctional polymerizable compound of Formula B:

[0158] [ka] During the ceremony, Rg is a polymerizable group, L is a linking group, j1 and j2 each independently represent an integer of 0 to 220, provided that the sum of j1 and j2 is 1 to 220; R A1 , R A2 , R A3 , R A4 , R A5 , and R A7 is independently, at each occurrence, C1-C6 alkyl, C3-C 12 Cycloalkyl, C1-C6 alkoxy, C4-C 12cyclic alkoxy, alkoxy-alkyleneoxy-alkyl, aryl (e.g., phenyl), aryl-alkyl (e.g., benzyl), haloalkyl (e.g., partially or fully fluorinated alkyl), siloxy, fluoro, or combinations thereof, wherein each alkyl group in the foregoing groups is optionally substituted with one or more hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, carbamate, carbonate, halo, phenyl, or benzyl; each cycloalkyl is optionally substituted with one or more alkyl, hydroxy, amino, amido, oxa, carbonyl, alkoxy, carbamate, carbonate, halo, phenyl, or benzyl; and each aryl is optionally substituted with one or more alkyl, hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, carbamate, carbonate, halo, phenyl, or benzyl; R A6 is siloxy, C1-C8 alkyl (e.g., C1-C4 alkyl, or butyl, or methyl), or aryl (e.g., phenyl), where alkyl and aryl may be optionally substituted with one or more fluorine atoms.

[0159] Formula B-1. Compounds of formula B can include compounds of formula B-1, which are compounds of formula B, wherein j1 is 0 and j2 is 1 to 220, or j2 is 1 to 100, or j2 is 1 to 50, or j2 is 1 to 20, or j2 is 1 to 5, or j2 is 1.

[0160] B-2. Compounds of formula B may include compounds of formula B-2, which are compounds of formula B, wherein j1 and j2 are independently 4 to 100, or 4 to 20, or 4 to 10, or 24 to 100, or 10 to 100.

[0161] B-3. ​​Compounds of formula B, B-1, and B-2 may include compounds of formula B-3, wherein R A1 , R A2 , RA3 , and R A4 is independently at each occurrence a C1-C6 alkyl or siloxy. Preferred alkyl is a C1-C3 alkyl, or more preferably methyl. Preferred siloxy is trimethylsiloxy.

[0162] B-4. Compounds of formula B, B-1, B-2, and B-3 may include compounds of formula B-4, wherein R A5 and R A7 are independently alkoxy-alkyleneoxy-alkyl, preferably independently of the formula CH3O-[CH2CH2O] p A compound of formula B, B-1, B-2, or B-3, which is a methoxy-capped polyethyleneoxyalkyl, -CH2CH2CH2, where p is an integer from 1 to 50.

[0163] B-5. Compounds of formula B, B-1, B-2, and B-3 may include compounds of formula B-5, wherein R A5 and R A7 is a compound of formula B, B-1, B-2, or B-3, wherein is independently siloxy, such as trimethylsiloxy.

[0164] B-6. Compounds of formula B, B-1, B-2, and B-3 may include compounds of formula B-6, wherein R A5 and R A7 is independently C1-C6 alkyl, alternatively C1-C4 alkyl, or alternatively butyl or methyl.

[0165] B-7. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, and B-6 may include compounds of formula B-7, wherein R A6is a C1-C8 alkyl, preferably a C1-C6 alkyl, more preferably a C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, or n-butyl). A6 is n-butyl.

[0166] B-8. The compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, and B-7 may include compounds of formula B-8, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, or B-7, where Rg includes styryl, vinyl carbonate, vinyl ether, vinyl carbamate, N-vinyl lactam, N-vinyl amide, (meth)acrylate, or (meth)acrylamide. Preferably, Rg includes (meth)acrylate, (meth)acrylamide, or styryl. More preferably, Rg includes (meth)acrylate or (meth)acrylamide. When Rg is (meth)acrylamide, the nitrogen group is R A9 may be substituted with R A9 is H, C1-C8 alkyl (preferably C1-C4 alkyl, e.g., n-butyl, n-propyl, methyl, or ethyl), or C3-C8 cycloalkyl (preferably C5-C6 cycloalkyl), where the alkyl and cycloalkyl are optionally substituted with one or more groups independently selected from hydroxyl, amide, ether, silyl (e.g., trimethylsilyl), siloxy (e.g., trimethylsiloxy), alkyl-siloxanyl (wherein the alkyl is itself optionally substituted with fluoro), aryl-siloxanyl (wherein the aryl is itself optionally substituted with fluoro), and silyl-oxaalkylene (wherein the oxaalkylene is itself optionally substituted with hydroxyl).

[0167] B-9. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, and B-8 may include compounds of formula B-9, wherein the linking group is selected from the group consisting of alkylene (preferably C1-C4 alkylene), cycloalkylene (preferably C5-C6 cycloalkylene), alkyleneoxy (preferably ethyleneoxy), haloalkyleneoxy (preferably haloethyleneoxy), amido, oxaalkylene (preferably containing 3-6 carbon atoms), A compound of Formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, or B-8, comprising a siloxanyl, alkylenesiloxanyl, carbamate, alkyleneamine (preferably a C1-C6 alkyleneamine), or a combination of two or more thereof, wherein the linking group is optionally substituted with one or more substituents independently selected from alkyl, hydroxyl, ether, amine, carbonyl, siloxy, and carbamate.

[0168] B-10. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-10, wherein the linking group is alkylene-siloxanyl-alkylene-alkyleneoxy- or alkylene-siloxanyl-alkylene-[alkyleneoxy-alkylene-siloxanyl] q -alkyleneoxy- (wherein q is 1 to 50).

[0169] B-11. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-11, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, wherein the linking group is C1-C6 alkylene, preferably C1-C3 alkylene, more preferably n-propylene.

[0170] B-12. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-12, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where the linking group is alkylene-carbamate-oxaalkylene. Preferably, the linking group is CH2CH2N(H)-C(=O)-O-CH2CH2-O-CH2CH2CH2.

[0171] B-13. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-13, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, in which the linking group is oxaalkylene. Preferably, the linking group is CH2CH2-O-CH2CH2CH2.

[0172] B-14. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-14, wherein the linking group is alkylene-[siloxanyl-alkylene] q -, where q is 1 to 50. An example of such a linking group is -(CH2)3-[Si(CH3)2-O-Si(CH3)2-(CH2)2] q -It is.

[0173] B-15. Compounds of Formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of Formula B-15, which are compounds of Formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where the linking group is alkyleneoxy-carbamate-alkylene-cycloalkylene-carbamate-oxaalkylene, where the cycloalkylene is optionally substituted with one, two, or three independently selected alkyl groups (preferably C1-C3 alkyl, more preferably methyl). An example of such a linking group is -[OCH2CH2] q -OC(=O)-NH-CH2-[1,3-cyclohexylene]-NHC(=O)O-CH2CH2-O-CH2CH2-, where the cyclohexylene is substituted with three methyl groups at the 1- and 5-positions.

[0174] B-16. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-16, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where Rg comprises styryl, the linking group is alkyleneoxy, and each alkylene in the alkyleneoxy is independently optionally substituted with hydroxyl. An example of such a linking group is -O-(CH)-. Another example of such a linking group is -O-CHCH(OH)CH-O-(CH)-.

[0175] B-17. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-17, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where Rg comprises styryl and the linking group is an alkyleneamine. An example of such a linking group is -NH-(CH2)3-.

[0176] B-18. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-18, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where the linking group is an oxaalkylene optionally substituted with hydroxyl, siloxy, or silyl-alkyleneoxy (the alkyleneoxy is itself optionally substituted with hydroxyl). An example of such a linking group is -CHCH(G)CH-O-(CH)-, where G is hydroxyl. In another example, G is RSiO-, two R groups are trimethylsiloxy, and the third is C1-C8 alkyl (preferably C1-C3 alkyl, more preferably methyl), or the third is C3-C8 cycloalkyl. In a further example, G is RSi-(CH2)3-O-CH2CH(OH)CH2-O-, two R groups are trimethylsiloxy, and the third is C1-C8 alkyl (preferably C1-C3 alkyl, more preferably methyl) or C3-C8 cycloalkyl. In yet a further example, G is a polymerizable group such as (meth)acrylate. Such compounds can function as crosslinkers.

[0177] B-19. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-19, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where Rg comprises a styryl and the linking group is an amine-oxaalkylene optionally substituted with a hydroxyl. An example of such a linking group is -NH-CHCH(OH)CH-O-(CH)-.

[0178] B-20. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-20, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where Rg comprises styryl and the linking group is alkyleneoxy-carbamate-oxaalkylene. An example of such a linking group is -O-(CH)-N(H)C(=O)O-(CH)-O-(CH)-.

[0179] B-21. Compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, and B-9 can include compounds of formula B-21, which are compounds of formula B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, or B-9, where the linking group is alkylene-carbamate-oxaalkylene. An example of such a linking group is -(CH)-N(H)C(=O)O-(CH)-O-(CH)-.

[0180] Formula C. The silicone-containing component of Formula A, B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-18, and B-21 can include compounds of Formula C, which are compounds of Formula A, B, B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-18, or B-21 having the following structure:

[0181] [ka] During the ceremony, R A8 is hydrogen or methyl, Z is O, S, or N(R A9 ), and L, j1, j2, R A1 , R A2 , R A3 , R A4 , R A5 , RA6 , R A7 , and R A9 is as defined in formula B or its various subformulas (e.g., B-1, B-2, etc.).

[0182] C-1. Compounds of formula C can include (meth)acrylates of formula C-1, which are compounds of formula C where Z is O.

[0183] C-2. Compounds of formula C may include (meth)acrylamides of formula C-2, where Z is N(R A9 ) and R A9 is H.

[0184] C-3. Compounds of formula C may include (meth)acrylamides of formula C-3, where Z is N(R A9 ) and R A9 is a C1-C8 alkyl that is unsubstituted or optionally substituted as described above. A9 Examples of R include CH3, -CH2CH(OH)CH2(OH), -(CH2)3-siloxanyl, -(CH2)3-SiR3, and -CH2CH(OH)CH2-O-(CH2)3-SiR3, where each R in the foregoing groups is independently selected from trimethylsiloxy, C1-C8 alkyl (preferably C1-C3 alkyl, more preferably methyl), and C3-C8 cycloalkyl. A9 Further examples include -(CH2)3-Si(Me)(SiMe3)2 and -(CH2)3-Si(Me2)-[O-SiMe2] 1~10 -CH3 is an example.

[0185] Formula D. Compounds of Formula C can include compounds of Formula D:

[0186] [ka] During the ceremony, R A8 is hydrogen or methyl, Z 1is O or N(R A9 ) and L 1 is an alkylene containing 1 to 8 carbon atoms or an oxaalkylene containing 3 to 10 carbon atoms, and L 1 is optionally substituted with hydroxyl; j2, R A3 , R A4 , R A5 , R A6 , R A7 , and R A9 is as defined in formula B or its various subformulas (e.g., B-1, B-2, etc.).

[0187] D-1. Compounds of formula D may include compounds of formula D-1, wherein L 1 is a C2-C5 alkylene optionally substituted with hydroxyl. 1 is n-propylene optionally substituted with hydroxyl.

[0188] D-2. Compounds of formula D may include compounds of formula D-2, wherein L 1 is an oxaalkylene containing 4 to 8 carbon atoms optionally substituted with hydroxyl. 1 is an oxaalkylene containing 5 or 6 carbon atoms optionally substituted with hydroxyl. Examples include -(CH)-O-(CH)- and -CHCH(OH)CH-O-(CH)-.

[0189] D-3. Compounds of formula D, D-1, and D-2 may include compounds of formula D-3, wherein Z 1 is O.

[0190] D-4. Compounds of formula D, D-1, and D-2 may include compounds of formula D-4, wherein Z 1 is N(R A9 ) and R A9is H.

[0191] D-5. Compounds of formula D, D-1, and D-2 may include compounds of formula D-5, wherein Z 1 is N(R A9 ) and R A9 is a C1-C4 alkyl optionally substituted with one or two substituents selected from hydroxyl, siloxy, and C1-C6 alkyl-siloxanyl-.

[0192] D-6. Compounds of formula D, D-1, D-2, D-3, D-4, and D-5 can include compounds of formula D-6, which are compounds of formula D, D-1, D-2, D-3, D-4, or D-5, where j2 is 1.

[0193] D-7. Compounds of formula D, D-1, D-2, D-3, D-4, and D-5 can include compounds of formula D-7, which are compounds of formula D, D-1, D-2, D-3, D-4, or D-5, wherein j2 is 2 to 220, or 2 to 100, or 10 to 100, or 24 to 100, or 4 to 20, or 4 to 10.

[0194] D-8. Compounds of formula D, D-1, D-2, D-3, D-4, D-5, D-6, and D-7 can include compounds of formula D-8, wherein R A3 , R A4 , R A5 , R A6 , and R A7 is independently C1-C6 alkyl or siloxy. A3 , R A4 , R A5 , R A6 , and R A7 are independently selected from methyl, ethyl, n-propyl, n-butyl, and trimethylsiloxy. More preferably, R A3 , R A4 , R A5 , RA6 , and R A7 is independently selected from methyl, n-butyl, and trimethylsiloxy.

[0195] D-9. Compounds of formula D, D-1, D-2, D-3, D-4, D-5, D-6, and D-7 can include compounds of formula D-9, wherein R A3 and R A4 are independently C1-C6 alkyl (e.g., methyl or ethyl) or siloxy (e.g., trimethylsiloxy), and R A5 , R A6 , and R A7 is independently C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, or n-butyl).

[0196] The silicone-containing component of formula E can include a multifunctional silicone-containing component. Thus, for example, the silicone-containing component of formula A can include a difunctional material of formula E:

[0197] [ka] During the ceremony, Rg, L, j1, j2, R A1 , R A2 , R A3 , R A4 , R A5 , and R A7 is as defined above for formula B or its various subformulas (e.g., B-1, B-2, etc.), L 2 is a linking group, Rg 1 is a polymerizable group.

[0198] E-1. Compounds of formula E may include compounds of formula E-1, wherein Rg and Rg 1 are compounds of formula E, each of which is a vinyl carbonate of the structure CH2=CH-OC(=O)-O- or CH2=C(CH3)-OC(=O)-O-.

[0199] E-2. Compounds of formula E may include compounds of formula E-2, wherein Rg and Rg 1 are each (meth)acrylates.

[0200] E-3. Compounds of formula E may include compounds of formula E-3, wherein Rg and Rg 1 are each (meth)acrylamides, and the nitrogen group is R A9 may be substituted with (R A9 is as defined above), a compound of formula E.

[0201] E-4. Suitable compounds of formulas E, E-1, E-2, and E-3 include compounds of formula E-4, which are compounds of formula E, E-1, E-2, or E-3, wherein j1 is 0 and j2 is 1 to 220, or j2 is 1 to 100, or j2 is 1 to 50, or j2 is 1 to 20.

[0202] E-5. Suitable compounds of formulas E, E-1, E-2, and E-3 include compounds of formula E-5, which are compounds of formula E, E-1, E-2, or E-3, wherein j1 and j2 are independently 4 to 100.

[0203] E-6. Suitable compounds of formulas E, E-1, E-2, E-3, E-4, and E-5 include compounds of formula E-6, wherein R A1 , R A2 , R A3 , R A4 , and R A5 are independently at each occurrence C1-C6 alkyl, preferably they are independently C1-C3 alkyl, or preferably each is methyl.

[0204] E-7. Suitable compounds of formula E, E-1, E-2, E-3, E-4, E-5, and E-6 include compounds of formula E-7, wherein R A7is an alkoxy-alkyleneoxy-alkyl, preferably of the formula CH3O-[CH2CH2O] p A compound of formula E, E-1, E-2, E-3, E-4, E-5, or E-6, which is a methoxy-capped polyethyleneoxyalkyl of the formula —CHCHCH, where p is an integer from 1 to 50, or from 1 to 30, or from 1 to 10, or from 6 to 10.

[0205] E-8. Suitable compounds of formula E, E-1, E-2, E-3, E-4, E-5, E-6, and E-7 include compounds of formula E-8, which are compounds of formula E, E-1, E-2, E-3, E-4, E-5, E-6, or E-7, wherein L comprises alkylene, carbamate, siloxanyl, cycloalkylene, amide, haloalkyleneoxy, oxaalkylene, or a combination of two or more thereof, and the linking group is optionally substituted with one or more substituents independently selected from alkyl, hydroxyl, ether, amine, carbonyl, and carbamate.

[0206] E-9. Suitable compounds of formula E, E-1, E-2, E-3, E-4, E-5, E-6, E-7, and E-8 include compounds of formula E-9, wherein L 2 comprises alkylene, carbamate, siloxanyl, cycloalkylene, amide, haloalkyleneoxy, oxaalkylene, or a combination of two or more thereof, and the linking group is optionally substituted with one or more substituents independently selected from alkyl, hydroxyl, ether, amine, carbonyl, and carbamate.

[0207] Examples of silicone-containing components suitable for use in the present invention include, but are not limited to, the compounds listed in the table below: When a compound in the table below contains a polysiloxane group, the number of SiO repeat units in such compound is preferably 3 to 100, more preferably 3 to 40, or even more preferably 3 to 20, unless otherwise specified.

[0208] [Table 1-1]

[0209] [Table 1-2]

[0210] Additional non-limiting examples of suitable silicone-containing components are listed in the table below. Unless otherwise specified, where applicable, j2 is preferably 1 to 100, more preferably 3 to 40, or even more preferably 3 to 15. In compounds containing j1 or j2, the sum of j1 and j2 is preferably 2 to 100, more preferably 3 to 40, or even more preferably 3 to 15.

[0211] [Table 2-1]

[0212] [Table 2-2]

[0213] The silicone-containing component may have an average molecular weight of from about 400 to about 4000 Daltons.

[0214] The silicone-containing component may be present in an amount of up to about 95% by weight, or from about 10 to about 80% by weight, or from about 20 to about 70% by weight of the reactive mixture (excluding diluent), based on all reactive components.

[0215] polyamide The reactive monomer mixture may include at least one polyamide. As used herein, the term "polyamide" refers to polymers and copolymers containing repeating units containing amide groups. Polyamides may include cyclic amide groups, non-cyclic amide groups, and combinations thereof, and may be any polyamide known to those skilled in the art. Non-cyclic polyamides include pendant non-cyclic amide groups that are capable of association with hydroxyl groups. Cyclic polyamides include cyclic amide groups that are capable of association with hydroxyl groups.

[0216] Examples of suitable acyclic polyamides include polymers and copolymers comprising repeat units of formulae G1 and G2,

[0217] [ka] In the formula, X is a direct bond, —(CO)—, or —(CONHR 44 )-, wherein R 44 is a C1-C3 alkyl group, and R 40 is H, a linear or branched chain substituted or unsubstituted C1-C4 alkyl group, R 41 is selected from H, straight or branched chain substituted or unsubstituted C1-C4 alkyl groups, amino groups having up to 2 carbon atoms, amido groups having up to 4 carbon atoms, and alkoxy groups having up to 2 carbon atoms; R 42 is selected from H, a linear or branched, substituted or unsubstituted C1-C4 alkyl group, or methyl, ethoxy, hydroxyethyl, and hydroxymethyl; R 43 is selected from H, a linear or branched, substituted or unsubstituted C1-C4 alkyl group, or methyl, ethoxy, hydroxyethyl, and hydroxymethyl; R 40 and R 41 the total number of carbon atoms in R is 8 or less, including 7, 6, 5, 4, 3, or less; 42 and R 43 The total number of carbon atoms in R is 8 or less, including 7, 6, 5, 4, 3, or less. 40 and R 41The total number of carbon atoms in R may be 6 or less, or 4 or less. 42 and R 43 The total number of carbon atoms in the alkyl group may be up to 6. As used herein, a substituted alkyl group includes an alkyl group substituted with an amine group, an amide group, an ether group, a hydroxyl group, a carbonyl group, or a carboxyl group, or a combination thereof.

[0218] R 40 and R 41 may be independently selected from H, a substituted or unsubstituted C1-C2 alkyl group, X may be a direct bond, and R 40 and R 41 R may be independently selected from H, a substituted or unsubstituted C1-C2 alkyl group. 42 and R 43 may be independently selected from H, substituted or unsubstituted C1-C2 alkyl groups, methyl, ethoxy, hydroxyethyl, and hydroxymethyl.

[0219] The acyclic polyamides of the present invention may comprise a majority of repeat units of Formula LV or Formula LVI, or the acyclic polyamides may comprise at least 50 mole percent, such as at least about 70 mole percent, and at least 80 mole percent, of repeat units of Formula G or Formula G1. Specific examples of repeat units of Formula G and Formula G1 include N-vinyl-N-methylacetamide, N-vinylacetamide, N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide, N-vinyl-2-methyl-propionamide, N-vinyl-N,N'-dimethylurea, N,N-dimethylacrylamide, methacrylamide, and repeat units derived from the acyclic amides of Formulas G2 and G3.

[0220] [ka]

[0221] Examples of suitable cyclic amides that can be used to form the cyclic polyamides include α-lactams, β-lactams, γ-lactams, δ-lactams, and ε-lactams. Examples of suitable cyclic polyamides include polymers and copolymers comprising repeat units of formula G4:

[0222] [ka] In the formula, R 45 is a hydrogen atom or a methyl group, f is a number from 1 to 10, and X is a direct bond, —(CO)—, or —(CONHR 46 )-, where R 46 is a C1-C3 alkyl group. In Formula LIX, f can be 8 or less, including 7, 6, 5, 4, 3, 2, or 1. In Formula G4, f can be 6 or less, including 5, 4, 3, 2, or 1. In Formula G4, f can be 2 to 8, including 2, 3, 4, 5, 6, 7, or 8. In Formula LIX, f can be 2 or 3. When X is a direct bond, f can be 2. In such cases, the cyclic polyamide can be polyvinylpyrrolidone (PVP).

[0223] The cyclic polyamide may comprise 50 mole percent or more of repeat units of formula G4, or the cyclic polyamide may comprise at least 50 mole percent of repeat units of formula G4, such as at least 70 mole percent, and at least 80 mole percent.

[0224] Polyamides may also be copolymers containing both cyclic and non-cyclic amide repeat units. The additional repeat units may be formed from monomers selected from hydroxyalkyl (meth)acrylates, alkyl (meth)acrylates, other hydrophilic monomers, and siloxane-substituted (meth)acrylates. Any of the monomers listed as suitable hydrophilic monomers may be used as comonomers to form the additional repeat units. Specific examples of additional monomers that can be used to form polyamides include 2-hydroxyethyl (meth)acrylate, vinyl acetate, acrylonitrile, hydroxypropyl (meth)acrylate, methyl (meth)acrylate and hydroxybutyl (meth)acrylate, dihydroxypropyl (meth)acrylate, polyethylene glycol mono(meth)acrylate, and mixtures thereof. Ionic monomers may also be included.Examples of ionic monomers include (meth)acrylic acid, N-[(ethenyloxy)carbonyl]-β-alanine (VINAL, CAS#148969-96-4), 3-acrylamidopropanoic acid (ACA1), 5-acrylamidopropanoic acid (ACA2), 3-acrylamido-3-methylbutanoic acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q salt or METAC), 2-Acrylamide-2-methylpropanesulfonic acid (AMPS), 1-propanaminium, N-(2-carboxyethyl)-N,N-dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-, inner salt (CBT), 1-propanaminium, N,N-dimethyl-N-[3-[(1-oxo-2-propen-1-yl)amino]propyl]-3-sulfo-, inner salt (SBT), 3,5-dioxa- Examples include 8-aza-4-phosphanundec-10-en-1-aminium, 4-hydroxy-N,N,N-trimethyl-9-oxo-, inner salt, 4-oxide (9CI) (PBT), 2-methacryloyloxyethyl phosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS), and 3-((3-(methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS).

[0225] The reactive monomer mixture may include both acyclic polyamides and cyclic polyamides or copolymers thereof. The acyclic polyamide may be any of the acyclic polyamides or copolymers thereof described herein, and the cyclic polyamide may be any of the cyclic polyamides or copolymers thereof described herein. The polyamide may be selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylmethylacetamide (PVMA), polydimethylacrylamide (PDMA), polyvinylacetamide (PNVA), poly(hydroxyethyl(meth)acrylamide), polyacrylamide, and copolymers and mixtures thereof.

[0226] The total amount of all polyamides in the reactive mixture can be in the range of 1 weight percent to about 35 weight percent, such as in the range of 1 weight percent to about 15 weight percent, and in the range of about 5 weight percent to about 15 weight percent, in all cases based on the total weight of the reactive components of the reactive monomer mixture.

[0227] Without being bound by theory, when used with silicone hydrogels, polyamides function as internal wetting agents. The polyamides may be non-polymeric, in which case they are incorporated into the silicone hydrogel as a semi-interpenetrating network. The polyamides are encapsulated or physically held within the silicone hydrogel. Alternatively, the polyamides may be polymeric, for example, as polyamide macromers or prepolymers, in which case they are covalently incorporated into the silicone hydrogel. Mixtures of polymeric and non-polymeric polyamides may also be used.

[0228] When a polyamide is incorporated into the reactive monomer mixture, the polyamide may have a weight average molecular weight of at least 100,000 daltons, greater than about 150,000, from about 150,000 to about 2,000,000 daltons, or from about 300,000 to about 1,800,000 daltons. High molecular weight polyamides can be used if they are compatible with the reactive monomer mixture.

[0229] Crosslinking agent It is generally desirable to add one or more crosslinking agents, also referred to as crosslinking monomers, multifunctional macromers, and prepolymers, to the reactive mixture. The crosslinking agent can be selected from difunctional, trifunctional, tetrafunctional crosslinkers, and mixtures thereof, including silicone-containing and non-silicone-containing crosslinkers. Non-silicone-containing crosslinkers include ethylene glycol dimethacrylate (EGDMA), tetraethylene glycol dimethacrylate (TEGDMA), trimethylolpropane trimethacrylate (TMPTMA), triallyl cyanurate (TAC), glycerol trimethacrylate, methacryloxyethyl vinyl carbonate (HEMAVc), allyl methacrylate, methylenebisacrylamide (MBA), and polyethylene glycol dimethacrylate, where the polyethylene glycol has a molecular weight of up to about 5000 daltons. The crosslinking agent is used in the reactive mixture in conventional amounts, for example, from about 0.000415 to about 0.0156 moles per 100 grams of reactive formulation. Alternatively, if the hydrophilic monomer and / or silicone-containing component is multifunctional due to molecular design or impurities, adding a crosslinker to the reactive mixture is optional. Examples of hydrophilic monomers and macromers that can act as crosslinkers and, if present, do not require the addition of additional crosslinkers to the reactive mixture include (meth)acrylate and (meth)acrylamide end-capped polyethers. Other crosslinkers will be known to those skilled in the art and can be used to prepare the silicone hydrogels of the present invention.

[0230] It may be desirable to select a crosslinker that has similar reactivity with one or more of the other reactive components in the formulation. In some cases, it may be desirable to select a mixture of crosslinkers with different reactivities to control some of the physical, mechanical, or biological properties of the resulting silicone hydrogel. The structure and morphology of the silicone hydrogel can also be affected by the diluent and curing conditions used.

[0231] To further increase the modulus and maintain tensile strength, multifunctional silicone-containing components, including macromers, crosslinkers, and prepolymers, may also be included. Silicone-containing crosslinkers may be used alone or in combination with other crosslinkers. An example of a silicone-containing component that can act as a crosslinker and, when present, does not require the addition of a crosslinking monomer to the reactive mixture, is α,ω-bismethacryloylpropyl polydimethylsiloxane.

[0232] Crosslinkers with rigid chemical structures and polymerizable groups capable of undergoing free radical polymerization can also be used. Non-limiting examples of suitable rigid structures include crosslinkers containing phenyl and benzyl moieties, such as 1,4-phenylenediacrylate, 1,4-phenylenedimethacrylate, 2,2-bis(4-methacryloxyphenyl)-propane, 2,2-bis[4-(2-acryloxyethoxy)phenyl]propane, 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane, and 4-vinylbenzyl methacrylate, as well as combinations thereof. The rigid crosslinkers can be present in an amount of about 0.5 to about 15, or about 2 to 10, or 3 to 7, based on the total weight of all reactive components. The physical and mechanical properties of the silicone hydrogels of the present invention can be optimized for specific applications by adjusting the components in the reactive mixture.

[0233] Non-limiting examples of silicone crosslinkers also include the multifunctional silicone-containing components described above, such as compounds of Formula E (and subformulas thereof) and the multifunctional compounds shown in the table above.

[0234] Further components If desired, the reactive monomer mixture may contain additional components such as, but not limited to, diluents, initiators, UV absorbers, visible light absorbers, photochromic compounds, pharmaceuticals, nutritional supplements, antimicrobial substances, colorants, pigments, copolymerizable dyes, non-polymerizable dyes, mold release agents, and combinations thereof.

[0235] Suitable types of diluents for silicone hydrogel reactive mixtures include alcohols having 2 to 20 carbon atoms, amides derived from primary amines having 10 to 20 carbon atoms, and carboxylic acids having 8 to 20 carbon atoms. Diluents can be primary, secondary, and tertiary alcohols.

[0236] Generally, the reactive components are mixed in a diluent to form a reactive mixture. Suitable diluents are known in the art. For silicone hydrogels, suitable diluents are disclosed in WO 03 / 022321 and U.S. Pat. No. 6,020,445, the disclosures of which are incorporated herein by reference. Suitable diluent classes for silicone hydrogel reactive mixtures include alcohols having 2 to 20 carbon atoms, amides having 10 to 20 carbon atoms derived from primary amines, and carboxylic acids having 8 to 20 carbon atoms. Primary and tertiary alcohols can be used. Preferred classes include alcohols having 5 to 20 carbon atoms and carboxylic acids having 10 to 20 carbon atoms. Specific diluents that may be used include 1-ethoxy-2-propanol, diisopropylaminoethanol, isopropanol, 3,7-dimethyl-3-octanol, 1-decanol, 1-dodecanol, 1-octanol, 1-pentanol, 2-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, tert-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2 ... Examples of suitable diluents include alcohol, 2-propanol, 1-propanol, ethanol, 2-ethyl-1-butanol, (3-acetoxy-2-hydroxypropyloxy)-propylbis(trimethylsiloxy)methylsilane, 1-tert-butoxy-2-propanol, 3,3-dimethyl-2-butanol, tert-butoxyethanol, 2-octyl-1-dodecanol, decanoic acid, octanoic acid, dodecanoic acid, 2-(diisopropylamino)ethanol, and mixtures thereof. Examples of amide diluents include N,N-dimethylpropionamide and dimethylacetamide.

[0237] Preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, 2-pentanol, t-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, decanoic acid, octanoic acid, dodecanoic acid, mixtures thereof, and the like.

[0238] More preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 1-dodecanol, 3-methyl-3-pentanol, 1-pentanol, 2-pentanol, t-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, mixtures thereof, and the like. When a diluent is present, there are generally no particular limitations on the amount of diluent present. When a diluent is used, the diluent may be present in an amount ranging from about 2 to about 70 weight percent, such as from about 5 to about 50 weight percent and from about 15 to about 40 weight percent, based on the total weight of the reactive mixture (including reactive and non-reactive compounds). Mixtures of diluents may also be used.

[0239] A polymerization initiator may be used in the reactive mixture, and may include at least one of those that generate free radicals at moderately high temperatures, such as lauryl peroxide, benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, and photoinitiator systems, such as aromatic alpha-hydroxyketones, alkoxyoxybenzoins, acetophenones, acylphosphine oxides, bisacylphosphine oxides, and tertiary amines plus alpha-diketones, and mixtures thereof. Specific examples of photoinitiators include 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-2-methyl-1-phenyl-propan-1-one, bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentylphosphine oxide (DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure 819), 2,4,6-trimethylbenzyldiphenylphosphine oxide and 2,4,6-trimethylbenzoyldiphenylphosphine oxide, benzoin methyl ester, and a combination of camphorquinone and ethyl 4-(N,N-dimethylamino)benzoate. Diazo thermal initiators such as azobisisobutyronitrile (AIBN), 2,2'-azobis(2-methylbutyronitrile) (AMBN), or similar compounds can also be used.

[0240] Commercially available visible light initiator systems include Irgacure® 819, Irgacure® 1700, Irgacure® 1800, Irgacure® 819, and Irgacure® 1850 (all from Ciba Specialty Chemicals) and Lucrin® TPO initiator (available from BASF). Commercially available UV photoinitiators include Darocur® 1173 and Darocur® 2959 (Ciba Specialty Chemicals). These and other photoinitiators that can be used are disclosed in Volume III, Photoinitiators for Free Radical Cationic & Anionic Photopolymerization, 2nd Edition by JV Crivello & K. Dietliker; edited by G. Bradley; John Wiley and Sons; New York; 1998. The initiator is used in the reactive mixture in an amount effective to initiate photopolymerization of the reactive mixture, for example, from about 0.1 to about 2 parts by weight per 100 parts of the reactive monomer mixture. Polymerization of the reactive mixture can be initiated using heat, visible or ultraviolet light, or other means, appropriately selected depending on the polymerization initiator used. Alternatively, initiation can be carried out using an electron beam without a photoinitiator. However, when a photoinitiator is used, preferred initiators are bisacylphosphine oxides, such as bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure® 819) or a combination of 1-hydroxycyclohexyl phenyl ketone and bis(2,6-dimethoxybenzoyl)-2,4-4-trimethylpentylphosphine oxide (DMBAPO).

[0241] The reactive mixture for making the ophthalmic devices of the present invention may include, in addition to the population of core-shell particles described herein, any of the polymerizable compounds and optional ingredients described above.

[0242] A preferred reactive mixture may include a hydroxyphenylphenanthroline of Formula I and a hydrophilic monomer.

[0243] A preferred reactive mixture may include a population of core-shell particles as described herein and a hydrophilic monomer selected from DMA, NVP, HEMA, VMA, NVA, methacrylic acid, and mixtures thereof. A mixture of HEMA and methacrylic acid is preferred.

[0244] A preferred reactive mixture may include a population of core-shell particles described herein, a hydrophilic monomer, and a silicone-containing component.

[0245] A preferred reactive mixture may include a population of core-shell particles as described herein, a hydrophilic monomer, and a silicone-containing component including a compound of formula D (or subformulas D-1, D-2, etc.).

[0246] A preferred reactive mixture may include a population of core-shell particles as described herein, a hydrophilic monomer selected from DMA, NVP, HEMA, VMA, NVA, and mixtures thereof, a silicone-containing component including a compound of formula D (or subformulas D-1, D-2, etc.), and an internal wetting agent.

[0247] A preferred reactive mixture may include a population of core-shell particles as described herein, a hydrophilic monomer selected from DMA, HEMA, and mixtures thereof, a silicone-containing component selected from 2-hydroxy-3-[3-methyl-3,3-di(trimethylsiloxy)silylpropoxy]-propyl methacrylate (SiMAA), mono-methacryloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (mPDMS), mono-(2-hydroxy-3-methacryloxypropyl)-propyl ether-terminated mono-n-butyl-terminated polydimethylsiloxane (OH-mPDMS), and mixtures thereof, and a wetting agent (preferably PVP or PVMA). For the hydrophilic monomer, a mixture of DMA and HEMA is preferred. For the silicone-containing component, a mixture of SiMAA and mPDMS is preferred.

[0248] The reactive mixture may contain optional ingredients such as, but not limited to, one or more initiators, internal wetting agents, crosslinkers, other UV blockers, and diluents.

[0249] Curing of Hydrogels and Lens Fabrication The reactive mixture may be formed by any method known in the art, such as by shaking or stirring, and used to form a polymeric article or device by known methods. The reactive components are mixed together, either with or without a diluent, to form the reactive mixture.

[0250] For example, hydrogels can be prepared by mixing the reactive components and optionally a diluent with a polymerization initiator and curing under appropriate conditions to form an article that can then be formed into a suitable shape by lathing, cutting, etc. Alternatively, the reactive mixture can be placed in a mold and then cured to form a suitable article.

[0251] A method of making a silicone hydrogel contact lens may include preparing a reactive monomer mixture, transferring the reactive monomer mixture to a first mold, placing a second mold over the first mold filled with the reactive monomer mixture, and curing the reactive monomer mixture by free radical copolymerization to form a silicone hydrogel in the shape of a contact lens.

[0252] The reactive mixture may be cured via any known process for shaping reactive mixtures in the production of contact lenses, including rotational molding and static molding. Rotational molding processes are disclosed in U.S. Patent Nos. 3,408,429 and 3,660,545, and static molding processes are disclosed in U.S. Patent Nos. 4,113,224 and 4,197,266. The contact lenses of the present invention may be formed by direct molding of silicone hydrogels, which is economical and allows precise control over the final shape of the hydrated lens. In this method, the reactive mixture is placed into a mold having the shape of the desired final silicone hydrogel, and the reactive mixture is subjected to conditions that polymerize the monomers, thereby producing a polymer of the approximate shape of the desired final product.

[0253] After curing, the lens may be subjected to extraction to remove unreacted components and release the lens from the lens mold. Extraction may be performed using conventional extraction fluids, such as organic solvents such as alcohols, or may be extracted using aqueous solutions.

[0254] An aqueous solution is a solution containing water. The aqueous solution of the present invention may contain at least about 20 weight percent water, or at least about 50 weight percent water, or at least about 70 weight percent water, or at least about 95 weight percent water. The aqueous solution may also contain additional water-soluble ingredients, such as inorganic salts or release agents, wetting agents, slip agents, pharmaceutical ingredients, and nutraceutical compounds, or combinations thereof. A release agent is a compound or mixture of compounds that, when combined with water, reduces the time required to remove a contact lens from a mold compared to the time required to remove a contact lens using an aqueous solution without the release agent. The aqueous solution may not require special handling, such as purification, recycling, or special disposal.

[0255] Extraction may occur, for example, via immersion of the lens in an aqueous solution or exposure to a stream of aqueous solution. Extraction may also include, for example, one or more of: heating the aqueous solution; agitating the aqueous solution; increasing the concentration of a release agent in the aqueous solution to a level sufficient to cause lens release; mechanical or ultrasonic agitation of the lens; and incorporating at least one filter aid or extraction aid into the aqueous solution to a concentration sufficient to facilitate adequate removal of unreacted components from the lens. The foregoing, with or without the addition of heat, vibration, or both, may be performed in a batch or continuous process.

[0256] To facilitate leaching and demolding, it may be desirable to apply physical agitation. For example, the lens mold part to which the lens is attached can be vibrated or moved back and forth in the aqueous solution. Other methods may include passing ultrasound through the aqueous solution.

[0257] The lenses may be sterilized by known means, such as, but not limited to, autoclaving.

[0258] The silicone hydrogel ophthalmic devices (e.g., contact lenses) described herein preferably have one or more (and in some cases all) of the following properties. All values ​​are preceded by "about," and the device may have any combination of the listed properties. Properties can be determined by methods known to those skilled in the art, for example, as described in U.S. Pregrant Publication No. 2018 / 0037690, which is incorporated herein by reference. [H2O]%: at least 20%, or at least 25% Haze: 30% or less, or 10% or less Kruss DCA (°): 100° or less, or 50° or less Tensile modulus (psi): 120 or less, or 80 to 120 Dk (barrel) at least 80, or at least 100, or at least 150, or at least 200 Elongation at break: at least 100

[0259] With regard to ionic silicone hydrogels, the following properties (in addition to those mentioned above) may also be desirable: Lysozyme uptake (μg / lens): at least 100, or at least 150, or at least 500, or at least 700 Polyquaternium 1 (PQ1) uptake (%): 15 or less, or 10 or less, or 5 or less

[0260] Tablet Formation In some embodiments, the system can include an indicator encapsulated within the tablet. The tablet can be optically transparent. The tablet can be formed from a porous polymeric film formed from a thermoplastic polymer. The thermoplastic polymer can have a T above 121°C. g The porous polymer membrane may have a pore size larger than the pore size of the capping agent but smaller than the average particle size of the nanoparticle population. The pore size of the porous polymer membrane may be 5 nm to 75 nm, for example, 5 nm to 20 nm, 5 nm to 30 nm, 5 nm to 40 nm, 5 nm to 50 nm, 5 nm to 60 nm, or 20 nm to 75 nm.

[0261] Other uses and applications The systems disclosed herein may also be useful in the pesticide, food, and / or medical industries. The systems and methods may be used to indicate the amount of time that has elapsed since a trigger event occurred. This method may be used, for example, to visually indicate the amount of time that has elapsed since an item was removed from its packaging, the amount of time that has elapsed since an item or composition was prepared, and / or the length of time that an item has been in use. In some embodiments, the indicator may function as a compliance indicator. For example, the indicator may indicate when a desired amount of time has elapsed since the item was removed from its packaging. For example, the indicator may indicate when the item needs to be replaced. In some embodiments, the system may be used in bandages, orthodontic devices, implantable medical devices, or ophthalmic devices. For example, it may indicate when an orthodontic device, such as a retainer, expander, positioner, or spacer, needs to be replaced. It may also indicate when a bandage needs to be replaced.

[0262] The following examples are intended to further illustrate certain aspects of the materials and methods described herein, and are not intended to limit the scope of the claims. [Example]

[0263] Example 1: Synthesis of nanoparticle-type optical indicators Gold nanoparticles were synthesized by a seed-mediated method. First, a seed precursor was synthesized using a single-pot nucleation process. Solutions of gold(III) chloride hydrate (Sigma-Aldrich) and trisodium citrate dihydrate (Sigma-Aldrich) were dissolved in 20 ml of MilliQ water (18.2 MΩ cm, 20 °C, Millipore Sigma) in a glass scintillation vial (VWR) at 2.5 × 10 s. -4 and 10 -4The solution was prepared to a final concentration of 0.1 M. Unless otherwise specified, MilliQ water was used to prepare aqueous solutions throughout the remainder of the examples. Then, 60 μl of freshly prepared ice-cold sodium borohydride (0.1 M, Sigma-Aldrich) was added to the vial with vigorous stirring (2000 rpm), and the solution was left stirring for 1 minute while the seed precursor nucleated. The seed precursor was left overnight in the dark at ambient conditions. The seed precursor solution was then syringe filtered (0.2 μm, VWR) and stored in the dark at 4 °C until use.

[0264] Gold nanoparticles were synthesized with different sizes, shapes, and capping agents. , Se methyltrimethylammonium bromideTo grow nanoparticles capped with CTAB, gold(III) chloride hydrate (0.64 ml, 11 mM) and silver nitrate (0.096 ml, 0.01 M, Sigma-Aldrich) were added to a 15 ml solution of CTAB (1.466 mM) in a 20 ml scintillation vial under moderate stirring (900 rpm). The solution was allowed to stir for 1 min. L-ascorbic acid (0.103 ml, 0.1 M) was then added dropwise. Upon addition of the last drop, nanoseed precursor (0.6 ml) was immediately added and stirred moderately for 1.5 min. This sample is designated as Index 1 (I1). To grow red-colored nanoparticles capped with poly(vinylpyrrolidone) (PVP, Sigma-Aldrich), the process was repeated, but the silver nitrate and CTAB were omitted. Instead, gold(III) chloride hydrate was added to a solution of PVP (200 mM). This sample is designated I2. To grow red-colored nanoparticles capped with sodium dodecyl sulfate (SDS, Sigma-Aldrich), PVP was replaced with sodium iodide (0.25 mM) and SDS (24 mM) during synthesis. This sample is designated I3. To grow red-colored nanoparticles capped with Pluronic F-127 (Sigma-Aldrich), PVP was replaced with Pluronic F-127 (40 mM) during synthesis. This sample is designated I4. To grow nanoparticles exhibiting a blue color, gold(III) chloride hydrate (0.64 ml, 11 mM) and silver nitrate (0.192 ml, 0.01 M, Sigma-Aldrich) were added to a 15 ml solution of CTAB (7.33 mM) in a 20 ml scintillation vial under moderate stirring (900 rpm). The solution was allowed to stir for 1 minute. L-ascorbic acid (0.103 mL, 0.1 M, Sigma-Aldrich) was then added dropwise. Upon addition of the last drop, nanoseed precursor (240 μl) was immediately added and stirred moderately for 5 minutes. This sample is designated I5. To grow blue-colored nanoparticles capped with Tween 80 (Sigma-Aldrich), the respective process was repeated, but CTAB was replaced with Tween 80 (5 mM) during synthesis. This sample is designated I6.To grow SDS-capped, blue-colored nanoparticles, the respective process was repeated, but CTAB was replaced with SDS (24 mM) during synthesis. This sample is designated I7. The sample was centrifuged (15,000 rcf, 15 min) and resuspended in the desired concentration of capping agent, as indicated.

[0265] Example 2: Evaluation of discrete threshold-based color transitions of indicators in fixed microwell plates To assess whether the color transition of our indicators is indeed rapid and based on a discrete concentration threshold of the capping agent, we first prepared a three-fold concentrated solution of simulated tear fluid (STF) by dissolving sodium chloride (20.34 g / L, Sigma-Aldrich), sodium bicarbonate (6.54 g / L, Sigma-Aldrich), calcium chloride (0.192 g / L, Sigma-Aldrich), and potassium chloride (4.14 g / L, Sigma-Aldrich) in MilliQ water. We centrifuged solutions of the I5-color change indicator (15,000 rcf, 15 min, three times), concentrated them two-fold, and resuspended them in various concentrations of CTAB (1.6 mM, 6.4 mM, or 25.6 mM). In addition, we centrifuged solutions of the I4-color retention indicator, concentrated them two-fold, and resuspended them in MilliQ water. For the color-to-color (purple-to-red) transition, each concentrated solution of I4 was mixed with an aliquot of I5, and 200 μl of each solution was added to adjacent wells in a 96-well microplate (VWR). The microplate was then imaged (Figure 1B, top). The critical micelle concentration (CMC) of CTAB is approximately 1 mM at room temperature; therefore, the final CTAB concentrations in the mixtures were chosen to be slightly below (0.8 mM), above (3.2 mM), and significantly above (12.8 mM) the CMC. Immediately after the initial image, 100 μl of 3x concentrated STF was added to each well, diluting the STF concentration to 1x. Upon addition of STF, I5 (0.8 mM) began to instantly lose color, revealing a red color, and the color change saturated within 10 minutes (Figure 1B, bottom). The mixtures with I5 (3.2 mM) and I5 (12.8 mM) remained purple, demonstrating no color loss (Figure 1B, bottom). Collectively, the results indicated that capping agent concentrations near the CMC resulted in rapid color loss, while those with higher capping agent concentrations showed no color change. Additionally, the results indicated that the color retention index could be used in combination with the color change index to achieve discrete color-to-color transitions.

[0266] Example 3: Programming the activation time of an indicator in a container To evaluate the activation properties of the indicators in the container, we tested the indicators in dialysis cassettes (Thermo Fisher Scientific) with a molecular weight cutoff (MWCO) between the size of the indicator and the molecular weight of the capping agent. Thus, the capping agent can be released from the container while the indicator is retained. Unless otherwise noted, all tests were performed using dialysis cassettes with a MWCO of 3.5 kDa, at 37°C (in an incubator, VWR), and 1x STF.

[0267] Programmable color to clear transition For the color-to-clear transition, the I1 solution was centrifuged (15,000 rcf, 10 min, 3 times), resuspended in various concentrations of CTAB (one per centrifugation round), and loaded into a hydration cassette. The I1-containing vessel was imaged (starting image, time: 0 h) and placed in a beaker containing sufficient STF (1x, 350 ml) to completely immerse the cassette. The vessel was then imaged (times: 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 7 h, 8 h, 24 h, and then at each subsequent 24-h interval) to characterize the color progression. The STF in the beaker was periodically replaced with fresh STF (1x, 350 ml). The indicator was a discrete threshold response (Figure 1C-E, and Figure 2), initially demonstrating a color-to-clear transition that was programmable based on the concentration of capping agent in the cassette (time: 0 h) (Figure 3).

[0268] Programmable color to color to clear transition For the color → color → clear transition, solutions of I1 and I6 were centrifuged (15,000 rcf, 10 min, 3 times), resuspended in various concentrations of CTAB and Tween 80 (one per round of centrifugation), concentrated 2x, mixed, and loaded into a hydration cassette. The two indicator-containing containers were imaged as described above and placed in a beaker containing the STF. As shown in Figure 4, the indicators could be independently programmable, where the initial concentrations of CTAB and Tween 80 were 2 mM and 0.015 mM (top row) or 4 mM and 0.015 mM (bottom row). Samples also showed that I6 activated at the 1-hour mark in both samples when the capping agent concentration was identical, while I1 activated at the 5-day (top row) or 9-day (bottom row) mark based on different capping agent concentrations.

[0269] Delaying the activation of indicators in the vessel I1 and I7 were centrifuged (15,000 rcf, 10 min, 3 times), resuspended in capping agent concentrations above their respective CMCs (1.5 mM and 10 mM, respectively), and loaded into hydration cassettes. The indicator-containing containers were imaged (start image, time: 0 h) and placed in beakers containing STFs with equimolar concentrations of their respective capping agents, which were then imaged as described above. As shown in Figure 5, the color transition of the indicators in the containers was demonstrated to be delayed indefinitely, as the net concentration of capping agent remained consistent.

[0270] color retention index Color-to-color transitions can be achieved using a mixture of color loss and color retention indicators. The capping agent of the color retention indicator does not diffuse out of the container. The capping agent can be retained in the container by the container having a lower MWCO than the molecular weight of the color retention capping agent. In another embodiment, the capping agent can be strongly associated with the indicator, such that there is significant net diffusion of the capping agent out of the container. To demonstrate that I2 and I4 are two examples of the latter type of color retention indicator, solutions of I2 and I4 were centrifuged (15,000 rcf, 10 min, 3 times), resuspended in MilliQ water (once per round of centrifugation), and placed in a hydration cassette. The indicator-containing container was imaged (starting image, time: 0 h) and then placed in a beaker containing STF, which was imaged (times: 1 h, 2 h, 4 h, 8 h, 24 h, then at each 24-hour interval up to 1 week, then at each weekly interval). The STF was periodically replaced with fresh STF (1x). The color retention index shows that the colors were retained as shown in FIG.

[0271] Programmable Color → Color Transitions For the color-to-color transition, solutions I4 and I7 were centrifuged (15,000 rcf, 10 min, 3 times), resuspended in MilliQ water and different SDS concentrations (one per round of centrifugation), concentrated 2x, mixed, and loaded into a hydration cassette. These vessels were imaged (start time), placed in a beaker containing STF (1x), and imaged as described above. Figure 7 shows the purple-to-red color transition that occurred in the vessel at an initial SDS concentration of 8.5 mM.

[0272] Example 4: Incorporation of indicators into contact lenses and stability testing under sterilization conditions and consumer liquids To prepare the indicators for subsequent integration into biomedical devices, solutions of I3 and I6 were centrifuged (15,000 rcf, 10 min, 3 times), resuspended in MilliQ water and equimolar Tween 80 (one per round of centrifugation), concentrated 10-fold, mixed with poly(ethylene glycol) (PEG, final concentration: 50 mM, 6 kDa or 20 kDa, Sigma-Aldrich), and dried under vacuum. Dried indicator flakes were placed on a track-etched polycarbonate membrane (pore size: 15 nm, Sigma-Aldrich). A second polycarbonate membrane was then placed on top, sandwiching the indicator. A piece of filter paper was placed on top of the second polycarbonate membrane. A flat, solid stainless steel sealant was heated with a heat gun (Wagner Spray Tech, set at approximately 500°C for 6 minutes, approximately 1 cm from the heated surface) and pressed against the filter paper (1 minute). The filter paper was then removed, and a hollow stainless steel cutter with a sharp tip was heated as described above and pressed against the sealing membrane (1 minute). This process formed a container containing the indicator (Figure 8A). I3 and I6 were resuspended in their containers in solutions of MilliQ water and Tween 80, respectively. In a glove box, three drops of Etafilcon A monomer mixture were placed into a posterior contact lens mold, the I3- or I6-containing container was placed in the monomer mixture, three drops of the monomer mixture were added, and the container was embedded in the solution. The solution was then cured under UV light (20 minutes). The contact lens was placed in a water bath (60°C) and removed from the mold. The contact lenses containing the I3 and I6 containers were then placed in contact lens packing solution and placed in contact lens packing solution with equimolar Tween 80. Figures 8B and 8D show contact lenses with containers containing I6 or I3, respectively.

[0273] To form the indicator within the ring structure, a 2 μl droplet of PEG was added onto the polycarbonate membrane and allowed to dry. Then, a 2 μl droplet of the prepared solution of I3 was added to the dried PEG. The indicator solution was allowed to dry on the ring structure. The sandwiched polycarbonate membranes were contacted and sealed during the sealing process to maintain the ring structure after the indicator was resuspended. The remainder of the process for sealing, cutting, resuspending, and embedding the indicator-containing container and forming the indicator-containing contact lens was repeated from above. Figure 8C shows a contact lens with an I3-containing container within a ring structure embedded within the lens.

[0274] The indicators were tested for stability against autoclaving and various reagents. The prepared solution of I3 (Figure 8E) and the mixture of I4 and I7 (Figure 8F) were autoclaved and remained colloidally stable thereafter. The prepared solution of I1 was placed in a dialysis cassette. The containers were then placed in solutions to demonstrate stability against boric acid (0.5%, Sigma-Aldrich), disodium ethylenediaminetetraacetic acid (EDTA, 0.07%, Sigma-Aldrich), sorbitol (1.0%, Sigma-Aldrich), sodium citrate (0.65%, Sigma-Aldrich), 2-amino-2-methyl-1-propanal (0.001%, Sigma-Aldrich), Tetronic 904 (0.05%, Sigma-Aldrich), Aldox (0.0005%, Sigma-Aldrich), polyquaternium-1 (0.0005%, Toronto Research Chemicals), (0.2%, Sigma-Aldrich), and PureMoist lens cleaning solution (Figure 8G).

[0275] The systems, methods, compositions, and devices of the appended claims are not limited in scope by the specific materials and devices described herein, but are intended as examples of some aspects of the claims. Any systems, methods, compositions, and devices that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the systems, methods, compositions, and devices in addition to those shown and described herein are intended to fall within the scope of the appended claims. Furthermore, although only certain representative systems, methods, compositions, and devices disclosed herein are specifically described, other combinations of systems, methods, compositions, and devices are also intended to fall within the scope of the appended claims, even if not specifically set forth. Thus, although combinations of elements, components, or components may be explicitly referred to hereinafter, other combinations of elements, components, and components are included, even if not explicitly set forth.

[0276] As used herein, the term "comprising" and variations thereof are open, non-limiting terms used synonymously with the term "including" and variations thereof. While the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" can be used to provide more specific embodiments of the present invention and are disclosed. All numbers expressing geometric shapes, dimensions, and the like used in the specification and claims should be understood at a minimum and are not intended to limit the application of the doctrine of equivalents to the scope of the claims and should not be construed in light of the number of significant digits and ordinary rounding techniques.

[0277] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. Publications cited herein and the material for which they are cited are specifically incorporated by reference.

[0278] [Embodiment] (1) A system for visually indicating the amount of time that has elapsed since an item was removed from a package, comprising: an indicia disposed on or within the article, the article being enclosed within a sealable container of the package; and a trigger disposed within the container and in contact with the indicator; A system wherein the indicator responds to a change in the concentration of the trigger in contact with the indicator. (2) The system of embodiment 1, wherein the trigger is present in the container at a static concentration. (3) The system of embodiment 1, wherein the indicator comprises an optical indicator. (4) The system of embodiment 3, wherein the optical indicator includes a visible indicator. (5) A system described in any one of embodiments 1 to 4, wherein removal of the item from the container induces a change in the concentration of the trigger in contact with the indicator.

[0279] (6) The system of claim 5, wherein a change in the concentration of the trigger induces a change in the color of the indicator. (7) The system of claim 6, wherein the change in color comprises a change from a first color within the visible spectrum to a second color within the visible spectrum. (8) The system of claim 6, wherein the change in color comprises a change from a first color outside the visible spectrum to a second color within the visible spectrum. (9) The system of claim 6, wherein the change in color comprises a change from a first color within the visible spectrum to a second color outside the visible spectrum. (10) The system of any one of embodiments 1 to 9, wherein the indicator comprises a population of nanoparticles stabilized by a capping agent, and the trigger comprises a solution containing the capping agent in contact with the indicator.

[0280] (11) The system of embodiment 10, wherein the population of nanoparticles comprises a population of plasmonic nanoparticles. (12) The system of embodiment 11, wherein the population of plasmonic nanoparticles comprises gold, silver, platinum, or a combination thereof. (13) The system of any one of embodiments 10 to 12, wherein the ensemble nanoparticles have an average particle size of 5 nm to 100 nm, e.g., an average particle size of 20 nm to 60 nm, as measured by transmission electron microscopy (TEM). (14) The system of any one of embodiments 10 to 13, wherein the population of nanoparticles has a monodisperse particle size distribution. (15) The system according to any one of embodiments 10 to 14, wherein the nanoparticles have a polyhedral shape.

[0281] (16) The system of embodiment 15, wherein the nanoparticles have a cubic, octahedral, decahedral, cuboctahedral, tetrahedral, rhombic dodecahedral, truncated ditetragonal prismatic, or truncated bitetrahedral shape. (17) The system according to any one of embodiments 10 to 16, wherein the nanoparticles have a spherical, rod, conical, cylindrical, shell, or star shape. (18) The system according to any one of embodiments 10 to 17, wherein the nanoparticles have a uniform particle shape. (19) The system of any one of embodiments 10 to 17, wherein the nanoparticles comprise a mixture of particle shapes. (20) The system described in any one of embodiments 10 to 19, wherein the capping agent is non-covalently associated with the nanoparticle.

[0282] (21) The system described in any one of embodiments 10 to 20, wherein the capping agent is biocompatible. (22) The system described in any one of embodiments 10 to 21, wherein the capping agent comprises a surfactant. 23. The system of claim 22, wherein the surfactant comprises an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof. (24) The system of any one of embodiments 22-23, wherein the surfactant comprises a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof. (25) The system of any one of embodiments 10 to 24, wherein the capping agent comprises a polymer.

[0283] 26. The system of claim 25, wherein the polymer comprises polyvinylpyrrolidone, polyvinyl alcohol, a polyalkylene oxide such as polyethylene glycol, a cellulose-based polymer, tyloxapol, or a combination thereof. (27) The system of any one of embodiments 10 to 26, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the capping agent dissociates from the nanoparticles, thereby inducing aggregation of the population of nanoparticles. (28) The system of embodiment 27, wherein aggregation of the nanoparticle population results in a color change. (29) The system of embodiment 28, wherein the capping agent dissociates from the nanoparticles at a rate selected so that the color change indicates that a predetermined period of time has elapsed since the item was removed from the container. (30) The system described in embodiment 29, wherein the predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days.

[0284] (31) The system described in any one of embodiments 10 to 30, wherein the indicator comprises a first population of nanoparticles stabilized by a first capping agent and a second population of nanoparticles stabilized by a second capping agent, and the trigger comprises a solution containing the first capping agent and the second capping agent in contact with the indicator. (32) The system of embodiment 31, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the first capping agent dissociates from the first population of nanoparticles at a faster rate than the second capping agent dissociates from the second population of nanoparticles. 33. The system of claim 31, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the first capping agent dissociates from the first population nanoparticles, thereby inducing aggregation of the first population of nanoparticles and producing a first color change, and then the second capping agent dissociates from the second population nanoparticles, thereby inducing aggregation of the second population of nanoparticles and producing a second color change. (34) The system of embodiment 31, wherein the first capping agent dissociates from the first population of nanoparticles at a first rate selected such that the first color change indicates that a first predetermined period of time has elapsed since the item was removed from the container, and the second capping agent dissociates from the second population of nanoparticles at a second rate selected such that the second color change indicates that a second predetermined period of time has elapsed since the item was removed from the container. (35) The system described in embodiment 34, wherein the first predetermined period is 10 minutes to 2 weeks, and the second predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days.

[0285] (36) The system of any one of the preceding claims, wherein the indicator comprises a chromophore in combination with a dispersant, and the trigger comprises a solution comprising the dispersant in contact with the indicator. 37. The system of claim 36, wherein the chromophore comprises a fluorescein dye, a rhodamine dye, a coumarin, an azo dye, an anthraquinone dye, a benzodifuranone dye, a polycyclic aromatic carbonyl dye, an indigoid dye, a polymethine dye, an azacarbocyanine dye, a hemicyanine dye, a diazahemicyanine dye, a stryrl dye, a diarylcarbonium dye, a triarylcarbonium dye, a phthalocyanine dye, a quinophthalone dye, a triphenodioxazine dye, a formazan dye, a phenothiazine dye, such as methylene blue, azure A, azure B, and / or azure C, an oxazine dye, a thiazine dye, a naphtholactam dye, a diazahemicyanine dye, an azopyridone dye, an azobenzene dye, a xanthene dye, a leuco dye, or a combination thereof. (38) The system of any one of embodiments 36 to 37, wherein the dispersing agent is biocompatible. 39. The system of any one of embodiments 36 to 38, wherein the dispersant comprises a surfactant. 40. The system of embodiment 39, wherein the surfactant comprises an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof.

[0286] (41) The system of any one of embodiments 39 to 40, wherein the surfactant comprises a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof. 42. The system of any one of claims 36 to 41, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the dispersing agent dissociates from the chromophore, thereby inducing aggregation of the chromophore and producing a color change. 43. The system of claim 42, wherein the dispersing agent dissociates from the chromophore at a rate selected such that the color change indicates a predetermined period of time has elapsed since the item was removed from the container. (44) The system described in embodiment 43, wherein the predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days. (45) The system of embodiment 5, wherein a change in the concentration of the trigger induces a change in fluorescence in the indicator.

[0287] (46) The system of embodiment 45, wherein the change in fluorescence comprises a change in maximum emission wavelength, a change in fluorescence quantum yield, a change in the shape of the emission spectrum, a change in fluorescence lifetime, or a combination thereof. (47) The system of any one of embodiments 45 to 46, wherein the indicator comprises a fluorophore and the trigger comprises a solution comprising a quencher in contact with the indicator. (48) The system of embodiment 47, wherein the fluorophore comprises metal chalcogenide quantum dots, graphene quantum dots, carbon dots, graphite oxide, semiconductor (organic) polymer dots, ultrasmall metal nanoparticles, metal nanoclusters, fluorescently doped silica nanoparticles, fluorescently doped silica microparticles, fluorophore-functionalized dendrimers, upconversion nanoparticles, xanthenes such as fluorescein and / or rhodamine, naphthylamines, coumarins, acridines, N-(p-(2-benzoxazolyl)phenyl)maleimides, benzoxadiazoles, stilbenes, pyrenes, or combinations thereof. (49) The system of any one of embodiments 47 to 48, wherein the quencher comprises 6-carboxy-tetramethyl-rhodamine, 4-(4-dimethylaminophenylazo)benzoic acid (DABYL), tetramethylrhodamine (TAMRA), BHQ-0, BHQ-1, BHQ-2, BHQ-3, QSY-7, QSY-9, QSY-21, QSY-35, metal nanoparticles, graphene oxide, iron oxide nanoparticles, metal organic frameworks, carbon nanoparticles, quantum dots, or combinations thereof. (50) The system of any one of embodiments 47 to 49, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the quencher dissociates from the fluorophore, thereby inducing an increase in fluorescence.

[0288] 51. The system of claim 50, wherein the quencher dissociates from the fluorophore at a rate selected such that an increase in the fluorescence indicates that a predetermined period of time has elapsed since the item was removed from the container. (52) The system described in embodiment 51, wherein the predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days. (53) The system of any one of embodiments 45-46, wherein the indicator comprises a fluorophore in combination with a dispersing agent, and the trigger comprises a solution comprising the dispersing agent in contact with the indicator. (54) The system of embodiment 53, wherein the fluorophore comprises metal chalcogenide quantum dots, graphene quantum dots, carbon dots, graphite oxide, semiconductor (organic) polymer dots, ultrasmall metal nanoparticles, metal nanoclusters, fluorescently doped silica nanoparticles, fluorescently doped silica microparticles, fluorophore-functionalized dendrimers, upconversion nanoparticles, xanthenes such as fluorescein and / or rhodamine, naphthylamines, coumarins, acridines, N-(p-(2-benzoxazolyl)phenyl)maleimides, benzoxadiazoles, stilbenes, pyrenes, or combinations thereof. (55) The system of any one of embodiments 53 to 54, wherein the dispersing agent is biocompatible.

[0289] 56. The system of any one of embodiments 53 to 55, wherein the dispersant comprises a surfactant. 57. The system of claim 56, wherein the surfactant comprises an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof. (58) The system of any one of embodiments 56-57, wherein the surfactant comprises a phosphatide such as lecithin, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof. (59) The system of any of embodiments 53 to 58, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the dispersing agent dissociates from the fluorophore, thereby inducing aggregation of the fluorophore and producing a shift in maximum emission wavelength. 60. The system of claim 59, wherein the dispersing agent dissociates from the fluorophore at a rate selected such that a change in the maximum emission wavelength indicates that a predetermined period of time has elapsed since the article was removed from the container.

[0290] (61) The system described in embodiment 60, wherein the predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days. (62) The system of any one of embodiments 45 to 46, wherein the indicator comprises a first fluorophore, the trigger comprises a solution comprising a second fluorophore in contact with the indicator, and the first fluorophore and the second fluorophore comprise a fluorescence resonance energy transfer (FRET) pair. (63) The system of embodiment 62, wherein when the article is removed from the container and placed in contact with a solution containing a lower concentration of the trigger, the second fluorophore dissociates from the first fluorophore, thereby producing a change in maximum emission wavelength. (64) The system of embodiment 63, wherein the second fluorophore dissociates from the first fluorophore at a rate selected such that a change in the maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container. (65) The system described in embodiment 64, wherein the predetermined period is 30 minutes to 30 days, for example, 1 hour to 30 days.

[0291] (66) The system of any one of embodiments 1 to 65, wherein the article comprises a medical device. (67) The system of any one of embodiments 1 to 66, wherein the article comprises an ophthalmic device. (68) The system of any one of embodiments 1 to 67, wherein the article comprises a contact lens. (69) The system of embodiment 68, wherein the contact lens comprises a soft contact lens. (70) The system of any one of embodiments 68-69, wherein the contact lens comprises a polyurethane, a thiourethane, a poly(meth)acrylate, a silicone hydrogel, or a combination thereof.

[0292] (71) The system of any one of embodiments 68 to 70, wherein the contact lens comprises a polymer derived from the polymerization of a hydrophilic monomer, a silicone-containing component, or a combination thereof. (72) The system described in any one of embodiments 1 to 71, wherein the indicator is patterned on the article. (73) The system described in any one of embodiments 1 to 72, wherein the indicator is encapsulated in a tablet. (74) The system of embodiment 73, wherein the tablet is optically transparent. (75) The system of any one of embodiments 73 to 74, wherein the tablet is formed from a porous polymer membrane.

[0293] (76) The porous polymer membrane has a T exceeding 121°C. g 76. The system of embodiment 75, formed from a thermoplastic polymer having (77) The system of any one of embodiments 75 to 76, wherein the porous polymer membrane has a pore size of 5 nm to 75 nm. (78) The system of any one of embodiments 75 to 77, wherein the indicator comprises a population of nanoparticles stabilized by a capping agent, and the porous polymer membrane has a pore size larger than the capping agent but smaller than the average particle size of the population of nanoparticles. (79) The system of any one of embodiments 1 to 78, wherein the indicator is stable to autoclave. (80) The system of any one of claims 1, 10, or 31, wherein the index is a color retention index.

[0294] (81) The system of embodiment 80, wherein the capping agent does not diffuse out of the container.

Claims

1. 1. A system for visually indicating the amount of time that has elapsed since an item was removed from a package, comprising: a color retention indicator disposed on or within the article, the article being enclosed within a sealable container of the package; and a trigger disposed within the container and in contact with the color retention indicator; the color retention indicator responds to a change in concentration of the trigger in contact with the color retention indicator; the color retention indicator comprises a population of nanoparticles stabilized by a capping agent, and the trigger comprises a solution comprising a color change indicator capping agent in contact with the color retention indicator; when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the color change indicator capping agent dissociates from the nanoparticles, thereby inducing aggregation of the population of nanoparticles; aggregation of the nanoparticle population results in a color change; the color change indicator capping agent comprises cetyltrimethylammonium bromide, gold (III) chloride hydrate, and silver nitrate; the concentration of cetyltrimethylammonium bromide in the solution is 1.5 to 4 mM; the capping agent comprises a phosphatide, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, an alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, a polysorbate, polyvinylpyrrolidone, polyvinyl alcohol, a polyalkylene oxide, a cellulosic polymer, tyloxapol, or a combination thereof; the population of nanoparticles comprises a population of plasmonic nanoparticles; the population of plasmonic nanoparticles comprises gold, silver, platinum, or a combination thereof; the article is a contact lens, The system wherein the solution is a simulated tear solution for containing the contact lens in the solution.

2. The system of claim 1 , wherein the capping agent comprises polyvinylpyrrolidone, sodium dodecyl sulfate, poloxamer, polyoxyethylene sorbitan fatty acid ester, or a combination thereof.

3. The system of claim 1 or 2, wherein the capping agent comprises polyvinylpyrrolidone, sodium dodecyl sulfate, Pluronic™ F-127, and / or Tween™ 80.

4. The system of any one of claims 1 to 3, wherein the trigger is present in the container at a static concentration.

5. The system of any one of claims 1 to 4, wherein the color retention index comprises an optical index.

6. The system of claim 5 , wherein the optical indicator comprises a visible indicator.

7. The system of any one of claims 1 to 6, wherein removal of the article from the container induces a change in the concentration of the trigger in contact with the color retention indicator.

8. The system of claim 7 , wherein a change in the concentration of the trigger induces a change in the color of the color retention index.

9. The system of claim 8 , wherein the change in color comprises a change from a first color in the visible spectrum to a second color in the visible spectrum.

10. The system of claim 8 , wherein the change in color comprises a change from a first color outside the visible spectrum to a second color within the visible spectrum.

11. The system of claim 8 , wherein the change in color comprises a change from a first color within the visible spectrum to a second color outside the visible spectrum.

12. The system of any one of claims 1 to 11, wherein the population of nanoparticles has an average particle size of 5 nm to 100 nm as measured by transmission electron microscopy (TEM).

13. The system of any one of claims 1 to 12, wherein the population of nanoparticles has a monodisperse particle size distribution.

14. The system of any one of claims 1 to 13, wherein the nanoparticles have a polyhedral shape.

15. 15. The system of claim 14, wherein the nanoparticles have a cubic, octahedral, decahedral, cuboctahedral, tetrahedral, rhombic dodecahedral, truncated bisquare prism, or truncated double tetrahedral shape.

16. The system of any one of claims 1 to 15, wherein the nanoparticles have a spherical, rod, cone, cylinder, shell, or star shape.

17. The system according to any one of claims 1 to 16, wherein the nanoparticles have a uniform particle shape.

18. The system of any one of claims 1 to 16, wherein the nanoparticles comprise a mixture of particle shapes.

19. The system of any one of claims 1 to 18, wherein the capping agent is non-covalently associated with the nanoparticle.

20. The system of any one of claims 1 to 19, wherein the capping agent is biocompatible.

21. The system of any one of claims 1 to 20, wherein the capping agent comprises a surfactant.

22. 22. The system of any one of claims 1 to 21, wherein the capping agent dissociates from the nanoparticles at a rate selected so that the color change indicates that a predetermined period of time has elapsed since the item was removed from the container.

23. 23. The system of claim 22, wherein the predetermined period is between 30 minutes and 30 days.

24. 24. The system of claim 1, wherein the color retention index comprises a first population of nanoparticles stabilized by a first capping agent and a second population of nanoparticles stabilized by a second capping agent, and the trigger comprises the solution comprising the first capping agent and the second capping agent in contact with the color retention index.

25. 25. The system of claim 24, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the first capping agent dissociates from the first population of nanoparticles at a faster rate than the second capping agent dissociates from the second population of nanoparticles.

26. 25. The system of claim 24, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the first capping agent dissociates from the first population of nanoparticles, thereby inducing aggregation of the first population of nanoparticles and producing a first color change, and then the second capping agent dissociates from the second population of nanoparticles, thereby inducing aggregation of the second population of nanoparticles and producing a second color change.

27. 25. The system of claim 24, wherein the first capping agent dissociates from the first population of nanoparticles at a first rate selected such that a first color change indicates that a first predetermined period of time has elapsed since the item was removed from the container, and the second capping agent dissociates from the second population of nanoparticles at a second rate selected such that a second color change indicates that a second predetermined period of time has elapsed since the item was removed from the container.

28. 28. The system of claim 27, wherein the first predetermined period is between 10 minutes and 2 weeks, and the second predetermined period is between 30 minutes and 30 days.

29. 29. The system of any one of claims 1 to 28, wherein the color retention indicator further comprises a chromophore in combination with a dispersant, and the trigger comprises the solution comprising the dispersant in contact with the color retention indicator.

30. 30. The system of claim 29, wherein the chromophore comprises a fluorescein dye, a rhodamine dye, a coumarin, an azo dye, an anthraquinone dye, a benzodifuranone dye, a polycyclic aromatic carbonyl dye, an indigoid dye, a polymethine dye, an azacarbocyanine dye, a hemicyanine dye, a diazahemicyanine dye, a strilyl dye, a diarylcarbonium dye, a triarylcarbonium dye, a phthalocyanine dye, a quinophthalone dye, a triphenodioxazine dye, a formazan dye, a phenothiazine dye, an oxazine dye, a thiazine dye, a naphtholactam dye, an azopyridone dye, an azobenzene dye, a xanthene dye, a leuco dye, or a combination thereof.

31. 31. The system of claim 29 or 30, wherein the dispersing agent is biocompatible.

32. The system of any one of claims 29 to 31, wherein the dispersant comprises a surfactant.

33. 33. The system of claim 32, wherein the surfactant comprises an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof.

34. 34. The system of claim 32 or 33, wherein the surfactant comprises a phosphatide, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof.

35. 35. The system of any one of claims 29 to 34, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the dispersing agent dissociates from the chromophore, thereby inducing aggregation of the chromophore and producing the color change.

36. 36. The system of claim 35, wherein the dispersing agent dissociates from the chromophore at a rate selected so that the color change indicates that a predetermined period of time has elapsed since the item was removed from the container.

37. 37. The system of claim 36, wherein the predetermined period is between 30 minutes and 30 days.

38. The system of claim 7 , wherein a change in the concentration of the trigger induces a change in fluorescence in the color retention index.

39. 39. The system of claim 38, wherein the change in fluorescence comprises a change in maximum emission wavelength, a change in fluorescence quantum yield, a change in the shape of the emission spectrum, a change in fluorescence lifetime, or a combination thereof.

40. 40. The system of claim 38 or 39, wherein the color retention indicator comprises a fluorophore and the trigger comprises the solution comprising a quencher in contact with the color retention indicator.

41. 41. The system of claim 40, wherein the fluorophore comprises metal chalcogenide quantum dots, graphene quantum dots, carbon dots, graphite oxide, semiconducting (organic) polymer dots, ultrasmall metal nanoparticles, metal nanoclusters, fluorescently doped silica nanoparticles, fluorescently doped silica microparticles, fluorophore-functionalized dendrimers, upconversion nanoparticles, xanthene, naphthylamine, coumarin, acridine, N-(p-(2-benzoxazolyl)phenyl)maleimide, benzoxadiazole, stilbene, pyrene, or a combination thereof.

42. 42. The system of claim 40 or 41, wherein the quencher comprises 6-carboxy-tetramethyl-rhodamine, 4-(4-dimethylaminophenylazo)benzoic acid (DABYL), tetramethylrhodamine (TAMRA), BHQ-0™, BHQ-1™, BHQ-2™, BHQ-3™, QSY-7™, QSY-9™, QSY-21™, QSY-35™, metal nanoparticles, graphene oxide, iron oxide nanoparticles, metal organic frameworks, carbon nanoparticles, quantum dots, or combinations thereof.

43. 43. The system of any one of claims 40-42, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the quencher dissociates from the fluorophore, thereby inducing an increase in fluorescence.

44. 44. The system of claim 43, wherein the quencher dissociates from the fluorophore at a rate selected so that an increase in the fluorescence indicates that a predetermined period of time has elapsed since the item was removed from the container.

45. 45. The system of claim 44, wherein the predetermined period is between 30 minutes and 30 days.

46. 40. The system of claim 38 or 39, wherein the color retention indicator comprises a fluorophore in combination with a dispersant, and the trigger comprises the solution comprising the dispersant in contact with the color retention indicator.

47. 47. The system of claim 46, wherein the fluorophore comprises metal chalcogenide quantum dots, graphene quantum dots, carbon dots, graphite oxide, semiconducting (organic) polymer dots, ultrasmall metal nanoparticles, metal nanoclusters, fluorescently doped silica nanoparticles, fluorescently doped silica microparticles, fluorophore-functionalized dendrimers, upconversion nanoparticles, xanthene, naphthylamine, coumarin, acridine, N-(p-(2-benzoxazolyl)phenyl)maleimide, benzoxadiazole, stilbene, pyrene, or a combination thereof.

48. 48. The system of claim 46 or 47, wherein the dispersing agent is biocompatible.

49. The system of any one of claims 46 to 48, wherein the dispersant comprises a surfactant.

50. 50. The system of claim 49, wherein the surfactant comprises an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amphoteric surfactant, or a combination thereof.

51. 51. The system of claim 49 or 50, wherein the surfactant comprises a phosphatide, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, 3-[N,N-dimethyl(3-palmitoylaminopropyl)ammonio]-propanesulfonate, N-dodecyl-N,N-(dimethylammonio)butyrate, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, octadecanoic acid, poloxamer, poloxamine, alkylaryl polyether sulfonate, palmitic acid, dodecylphosphonic acid, sodium oleate, sodium octanoate, cetyltrimethylammonium bromide, tetrabutylammonium hydroxide titrant, sodium dodecylphosphonate, tetrabutylammonium palmitate, tetrabutylammonium laurate, polysorbate, or a combination thereof.

52. 52. The system of any one of claims 46-51, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the dispersing agent dissociates from the fluorophore, thereby inducing aggregation of the fluorophore and producing a shift in maximum emission wavelength.

53. 53. The system of claim 52, wherein the dispersing agent dissociates from the fluorophore at a rate selected such that a change in the maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container.

54. 54. The system of claim 53, wherein the predetermined period is between 30 minutes and 30 days.

55. 40. The system of claim 38 or 39, wherein the color retention indicator comprises a first fluorophore, the trigger comprises the solution comprising a second fluorophore in contact with the color retention indicator, and the first fluorophore and the second fluorophore comprise a fluorescence resonance energy transfer (FRET) pair.

56. 56. The system of claim 55, wherein when the article is removed from the container and placed in contact with the solution containing a lower concentration of the trigger, the second fluorophore dissociates from the first fluorophore, thereby producing a change in maximum emission wavelength.

57. 57. The system of claim 56, wherein the second fluorophore dissociates from the first fluorophore at a rate selected such that a change in the maximum emission wavelength indicates that a predetermined period of time has elapsed since the item was removed from the container.

58. 58. The system of claim 57, wherein the predetermined period is between 30 minutes and 30 days.

59. The system of any one of claims 1 to 58, wherein the article comprises a medical device.

60. 60. The system of any one of claims 1 to 59, wherein the contact lens is a soft contact lens.

61. 61. The system of any one of claims 1 to 60, wherein the contact lens comprises a polyurethane, a thiourethane, a poly(meth)acrylate, a silicone hydrogel, or a combination thereof.

62. 62. The system of any one of claims 1 to 61, wherein the contact lens comprises a polymer derived from the polymerization of hydrophilic monomers, silicone-containing components, or combinations thereof.

63. The system of any one of claims 1 to 62, wherein the color retention indicator is patterned on the article.

64. 64. The system of any one of claims 1 to 63, wherein the color retention index is autoclave stable.

65. The system of any one of claims 1 to 64, wherein the capping agent does not diffuse out of the container.

Images